EP3172964B1 - Parasiticidal compositions comprising an isoxazoline active agent, method and uses thereof - Google Patents

Parasiticidal compositions comprising an isoxazoline active agent, method and uses thereof Download PDF

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Publication number
EP3172964B1
EP3172964B1 EP16187099.3A EP16187099A EP3172964B1 EP 3172964 B1 EP3172964 B1 EP 3172964B1 EP 16187099 A EP16187099 A EP 16187099A EP 3172964 B1 EP3172964 B1 EP 3172964B1
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Prior art keywords
day
group
alkyl
composition
efficacy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP16187099.3A
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German (de)
English (en)
French (fr)
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EP3172964A1 (en
Inventor
Mark D. Soll
Joseph K. Rosentel
James Pate
Natalya Shub
Monica Tejwani-Motwani
Carol Belansky
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Boehringer Ingelheim Animal Health USA Inc
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Boehringer Ingelheim Animal Health USA Inc
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Application filed by Boehringer Ingelheim Animal Health USA Inc filed Critical Boehringer Ingelheim Animal Health USA Inc
Priority to PL16187099T priority Critical patent/PL3172964T3/pl
Priority to SI201231857T priority patent/SI3172964T1/sl
Priority to EP20190542.9A priority patent/EP3788874A1/en
Priority to RS20201351A priority patent/RS61048B1/sr
Publication of EP3172964A1 publication Critical patent/EP3172964A1/en
Publication of EP3172964B1 publication Critical patent/EP3172964B1/en
Application granted granted Critical
Priority to HRP20201745TT priority patent/HRP20201745T1/hr
Priority to CY2021015C priority patent/CY2021015I1/el
Priority to HUS2100024C priority patent/HUS2100024I1/hu
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A—HUMAN NECESSITIES
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    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
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    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Definitions

  • the present invention provides topical veterinary compositions comprising at least one isoxazoline active agent for controlling ectoparasites and endoparasites in animals; and these compositions for use in preventing or treating parasitic infections and infestations in animals.
  • ectoparasites such as insects
  • endoparasites such as filariae and other worms
  • domesticated animals such as cats and dogs, are often infested with one or more of the following ectoparasites:
  • Fleas are a particular problem because not only do they adversely affect the health of the animal or human, but they also cause a great deal of psychological stress. Moreover, fleas are also vectors of pathogenic agents in animals and humans, such as dog tapeworm ( Dipylidium caninum ).
  • ticks are also harmful to the physical and psychological health of the animal or human.
  • Major diseases which are caused by ticks include borrelioses (Lyme disease caused by Borrelia burgdorferi ), babesioses (or piroplasmoses caused by Babesia spp.) and rickettsioses (also known as Rocky Mountain spotted fever).
  • Ticks also release toxins which cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.
  • farm animals are also susceptible to parasite infestations.
  • cattle are affected by a large number of parasites.
  • a parasite which is very prevalent among farm animals is the tick genus Rhipicephalus , especially those of the species microplus (cattle tick), decoloratus and annulatus. Ticks such as Rhipicephalus microplus (formerly Boophilus microplus ) are particularly difficult to control because they live in the pasture where farm animals graze.
  • This species of ticks is considered a one-host tick and spends immature and adult stages on one animal before the female engorges and falls off the host to lay eggs in the environment. The life cycle of the tick is approximately three to four weeks.
  • Rhipicephalus microplus may infest found on buffalo, horses, donkeys, goats, sheep, deer, pigs, and dogs.
  • a heavy tick burden on animals can decrease production and damage hides as well as transmit diseases such as babesiosis ("cattle fever") and anaplasmosis caused by protozoan parasites.
  • helminthiasis which is most frequently caused by a group of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flukes). These parasites adversely affect the nutrition of the animal and cause severe economic losses in pigs, sheep, horses, and cattle as well as affecting domestic animals and poultry.
  • parasites which occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius and parasites which are found in the blood or other tissues and organs such as filarial worms and the extra intestinal stages of Strogyloides, Toxocara and Trichinella.
  • WO 2012/089623 describes topical localized isoxazoline formulations comprising glycofurol.
  • WO 2009/002809 and WO2007/079162 disclose isoxazolines, compositions thereof and their use as pesticides.
  • compositions comprising isoxazoline active agents alone or in combination with other active agents described in the documents above, there is a need for veterinary compositions and methods with improved efficacy, bioavailability, and spectrum of coverage to protect animals against endoparasites and/or ectoparasites.
  • Optimal compositions should provide contact and/or systemic activity, be efficacious, have a quick onset of activity, have a long duration of activity, and be safe to the animal recipient and their human owners. This invention addresses this need.
  • the present invention is directed to a topical veterinary composition for treating or preventing a parasitic infection or infestation in an animal selected from a cat and a dog, wherein said composition is in the form of a spot-on composition for application to a localized area on an animal, said composition comprising:
  • the present invention provides novel and inventive topical compositions in the form of spot-on formulations comprising at least one isoxazoline compound together with a pharmaceutically acceptable carrier or diluent that is suitable for topical application to an animal, wherein the carrier comprises dimethyl isosorbide (DMI).
  • a pharmaceutically acceptable carrier or diluent that is suitable for topical application to an animal, wherein the carrier comprises dimethyl isosorbide (DMI).
  • DMI dimethyl isosorbide
  • compositions include spot-on formulations that are applied to a localized area on an animal.
  • Topical spray, aerosol or foam formulations which typically include the active agent in lower concentrations, are also described herein. These formulations provide surprisingly effective protection of the animals against parasites for an extended period of time. The formulations also provide extremely rapid killing of parasites infesting animals.
  • the invention includes at least the following features:
  • animal is used herein to include all mammals, birds and fish and also include all vertebrate animals.
  • Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also includes an individual animal in all stages of development, including embryonic and fetal stages. In some embodiments, the animal will be a non-human animal.
  • fatty acid refers to carboxylic acids having from 4 to 26 carbon atoms.
  • fatty alcohol or "long-chain aliphatic alcohol” refer to aliphatic alcohols containing from 6 to 20 carbon atoms.
  • low melting refers to substances that are solids at room temperature but melt into liquids below 50° C.
  • alkyl refers to saturated straight, branched, cyclic, primary, secondary or tertiary hydrocarbons, including those having 1 to 20 atoms.
  • alkyl groups will include C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 or C 1 -C 4 alkyl groups.
  • C 1 -C 10 alkyl examples include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-
  • Cyclic alkyl groups or "cycloalkyl", which are encompassed by alkyl include those with 3 to 10 carbon atoms having single or multiple condensed rings.
  • cycloalkyl groups include C 4 -C 7 or C 3 -C 4 cyclic alkyl groups.
  • Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • alkyl groups described herein can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphoric acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the biological activity of the compounds of the invention, either
  • alkyl such as “alkylcycloalkyl,” “cycloalkylalkyl,” “alkylamino,” or “dialkylamino” will be understood to comprise an alkyl group as defined above linked to the other functional group, where the group is linked to the compound through the last group listed, as understood by those of skill in the art.
  • alkenyl refers to both straight and branched carbon chains which have at least one carbon-carbon double bond.
  • alkenyl groups may include C 2 -C 20 alkenyl groups.
  • alkenyl includes C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 4 alkenyl groups.
  • the number of double bonds is 1-3, in another embodiment of alkenyl, the number of double bonds is one or two. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule.
  • C 2 -C 10 -alkenyl groups may include more than one double bond in the chain. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propen
  • alkynyl refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond.
  • the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one or two.
  • alkynyl groups include from C 2 -C 20 alkynyl groups.
  • alkynyl groups may include C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 4 alkynyl groups.
  • Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule.
  • C 2 -C 10 -alkynyl refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-3-yl, 3-methyl
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted by one or more halogen atoms.
  • C 1 -C 4 -haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like
  • haloalkenyl refers to an alkenyl group, as defined herein, which is substituted by one or more halogen atoms.
  • haloalkynyl refers to an alkynyl group, as defined herein, which is substituted by one or more halogen atoms.
  • Alkoxy refers to alkyl-O-, wherein alkyl is as defined above.
  • alkenyloxy refers to alkyl-O-, wherein alkyl is as defined above.
  • alkenyloxy refers to the groups alkenyl-O-, alkynyl-O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl-
  • C 1 -C 6 -alkoxy examples include, but are not limited to, methoxy, ethoxy, C 2 H 5 -CH 2 O-, (CH 3 ) 2 CHO-, n-butoxy, C 2 H 5 -CH(CH 3 )O-, (CH 3 ) 2 CH-CH 2 O-, (CH 3 ) 3 CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylprop
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkylthio refers to haloalkyl-S- and cycloalkyl-S-where haloalkyl and cycloalkyl are as defined above.
  • alkylsulfinyl refers to alkyl-S(O)-, wherein alkyl is as defined above.
  • haloalkylsulfinyl refers to haloalkyl-S(O)- where haloalkyl is as defined above.
  • alkylsulfonyl refers to alkyl-S(O) 2 -, wherein alkyl is as defined above.
  • haloalkylsulfonyl refers to haloalkyl-S(O) 2 - where haloalkyl is as defined above.
  • alkylamino and dialkylamino refer to alkyl-NH- and (alkyl) 2 N- where alkyl is as defined above.
  • haloalkylamino refers to haloalkyl-NH- where haloalkyl is as defined above.
  • alkylcarbonyl alkoxycarbonyl
  • alkylaminocarbonyl alkylaminocarbonyl
  • dialkylaminocarbonyl refer to alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)- where alkyl, alkoxy, alkylamino and dialkylamino are as defined above.
  • haloalkylcarbonyl refers to the groups haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O)- and dihaloalkylamino-C(O)- where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings.
  • aryl groups include C 6 -C 10 aryl groups.
  • Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphtyl, phenylcyclopropyl and indanyl.
  • Aryl groups may be unsubstituted or substituted by one or more moieties selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl, alkenylsulfinyl, alky
  • aralkyl or "arylalkyl” refers to an aryl group that is bonded to the parent compound through a diradical alkylene bridge, (-CH 2 -) n , where n is 1-12 and where "aryl” is as defined above.
  • Heteroaryl refers to a monovalent aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, having one or more oxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings provided that the point of attachment is through a heteroaryl ring atom.
  • Preferred heteroaryls include pyridyl, piridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl benzofuranyl, and benzothiophenyl.
  • Heteroaryl rings may be unsubstituted or substituted by one or more moieties as described for aryl above.
  • Heterocyclyl refers to fully saturated or unsaturated, cyclic groups, for example, 3 to 7 membered monocyclic or 4 to 7 membered monocyclic; 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have one or more oxygen, sulfur or nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3 heteroatoms.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted by one or more moieties as described for aryl groups above.
  • Exemplary monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidin
  • bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl]or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
  • Halogen means the atoms fluorine, chlorine, bromine and iodine.
  • the designation of "halo" (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitutions from a single substitution to a perhalo substitution (e.g. as illustrated with methyl as chloromethyl (-CH 2 Cl), dichloromethyl (-CHCl 2 ), trichloromethyl (-CCl 3 )).
  • compositions of the invention may exist and be isolated as optically active and racemic forms.
  • Compounds having one or more chiral centers, including at a sulfur atom may be present as single enantiomers or diastereomers or as mixtures of enantiomers and/or diastereomers.
  • sulfoxide compounds may be optically active and may exist as single enantiomers or racemic mixtures.
  • compounds within the compositions of the invention may include one or more chiral centers, which results in a theoretical number of optically active isomers.
  • the compounds may comprise up to 2 n optical isomers.
  • the present invention encompasses the specific enantiomers or diastereomers of each compound as well as mixtures of different enantiomers and/or diastereomers of the compounds of the invention that possess the useful properties described herein.
  • the optically active forms can be prepared by, for example, resolution of the racemic forms by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
  • compositions of present invention may also be present in different solid forms such as different crystalline forms or in the form of an amorphous solid.
  • present invention encompasses different crystalline forms as well as amorphous forms of the inventive compounds.
  • compositions of the invention may exist as hydrates or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in the crystalline form.
  • the compositions of the invention may include hydrates and solvates of the active agents.
  • the compositions of the invention may include up to 15% (w/w), up to 20% (w/w), or up to 30% (w/w) of a particular solid form.
  • the term "acid salt” contemplates salts of the compounds with all pharmaceutically acceptable inorganic or organic acids.
  • Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid.
  • Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids.
  • the acids are straight chain or branched, saturated or unsaturated C 1 -C 20 aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C 6 -C 12 aromatic carboxylic acids.
  • acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, ⁇ -hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid.
  • dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and maleic acid.
  • An example of a tricarboxylic acid is citric acid.
  • Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms.
  • Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid.
  • Other acids include gluconic acid, glycoheptonic acid and lactobionic acid.
  • base salt contemplates salts of the compounds with all pharmaceutically acceptable inorganic or organic bases, including hydroxides, carbonates or bicarbonates of alkali metal or alkaline earth metals. Salts formed with such bases include, for example, the alkali metal and alkaline earth metal salts, including, but not limited to, as the lithium, sodium, potassium, magnesium or calcium salts. Salts formed with organic bases include the common hydrocarbon and heterocyclic amine salts, which include, for example, ammonium salts (NH4 + ), alkyl- and dialkylammonium salts, and salts of cyclic amines such as the morpholine and piperidine salts.
  • NH4 + ammonium salts
  • alkyl- and dialkylammonium salts alkyl- and dialkylammonium salts
  • salts of cyclic amines such as the morpholine and piperidine salts.
  • the invention provides topical veterinary compositions comprising effective amounts of at least one isoxazoline of formula (I) below, in combination and a pharmaceutically or veterinarily acceptable liquid carrier, wherein the carrier comprises dimethyl isosorbide: wherein:
  • W is O. In another embodiment, W is S.
  • a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CR 3 .
  • B 1 , B 2 and B 3 are each CR 2 .
  • W is O and A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CR 3 .
  • W is O; A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CR 3 ; and B 1 , B 2 and B 3 are each CR 2 .
  • a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CH.
  • B 1 , B 2 and B 3 are each CR 2 ; and R 2 is H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R 1 is C 1 -C 3 alkyl optionally substituted by one or more of R 6 ;
  • R 2 is independently H, halogen, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -CN; and each R 3 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloa l kyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN or -NO 2 .
  • the invention provides a composition comprising an isoxazoline of formula (I) wherein:
  • B 1 , B 2 and B 3 are independently CR 2 ; WisO; R 4 is H, C 1 -C 6 alkyl, C 2 -C 7 alkylcarbonyl or C 2 -C 7 alkoxycarbonyl; and R 5 is H, NR 11 R 12 or Q 1 ; or C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 4 cycloalkyl, C 4 -C 7 alkylcycloalkyl or C 4 -C 7 cycloalkylalkyl, each optionally substituted with one or more of R 7 .
  • R 4 is H; R 5 is C 1 -C 4 alkyl optionally substituted with one or more R 7 ; each R 7 is independently halogen or Q 2 ; and each Q 2 is independently phenyl, pyridinyl or thiazolyl.
  • R 1 is CF 3 ;
  • a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CR 3 ;
  • B 2 is CR 2 ; and each R 3 is independently H, C 1 -C 4 alkyl or -CN.
  • B 2 is CH; B 1 and B 3 are each CR 2 where each R 2 is independently halogen or C 1 -C 3 haloalkyl; A 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CR 3 ; R 3 is H; and n is 2.
  • R 1 is CF 3 ;
  • a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CR 3 ;
  • B 2 is CH; each of B 1 and B 3 are CR 2 ;
  • each R 3 is independently H or C 1 -C 4 alkyl;
  • each R 2 is independently halogen or C 1 -C 3 haloalkyl;
  • R 4 is H;
  • R 5 is C 1 -C 4 alkyl optionally substituted with one or more R 7 ;
  • R 7 is C 2 -C 7 alkylcarbonyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylcarbonyl, C 2 -C 7 haloalkoxycarbonyl, C 2 -C 7 haloalkylaminocarbonyl, C 3 -C 9 dihalo
  • R 1 is CF 3 ;
  • a 1 , A 2 , A 3 , A 4 , A 5 and A 6 are each CH;
  • B 2 is CH;
  • each of B 1 and B 3 are CR 2 ;
  • each R 2 is independently halogen or C 1 -C 3 haloalkyl;
  • R 4 is H;
  • R 5 is C 1 -C 4 alkyl optionally substituted with one or more R 7 ;
  • R 7 is C 2 -C 7 alkylaminocarbonyl, C 3 -C 9 dialkylaminocarbonyl, C 2 -C 7 haloalkylaminocarbonyl or C 3 -C 9 dihaloalkylaminocarbonyl.
  • a topical composition comprising an isoxazoline active agent of formula (I) is provided, wherein:
  • the isoxazoline compound is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide (Compound A).
  • compositions of the invention may include one or more compounds of the isoxazolines disclosed in WO 2007/079162 , WO 2007/075459 and US 2009/0133319 , WO 2007/070606 and US 2009/0143410 , WO 2009/003075 , WO 2009/002809 , WO 2009/024541 , WO 2005/085216 and US 2007/0066617 and WO 2008/122375 .
  • compositions comprising an isoxazoline active agent described in WO 2009/02451A2 and WO 2011/075591A1 , in combination with a pharmaceutically acceptable carrier or diluent.
  • compositions comprising compound 11-1 described in WO 2009/02451A2 , which has the structure: in combination with a pharmaceutically acceptable carrier or diluent described herein.
  • compositions comprising one or more of the isoxazoline compounds of formulae 1.001 to 1.025 and 2.001 to 2.018 described in WO 2011075591 in combination with a pharmaceutically acceptable carrier described herein: Compound No. (Z) p B 5 B 4 B 3 B 2 B 1 R 15 R 16 MS MH + RT (min) LCMS Method 1.001 3,5-Cl 2 C-H C-H C-H N H CH 2 C(O)NHCH 2 CF 3 582 2.21 1 1.002 3,5-Cl 2 C-H C-H C-H C-H N H CH 2 CF 3 525 2.32 1 1.003 3,5-(CF 3 ) 2 C-H C-H C-H C-H N CH 3 CH 2 CO 2 CH 3 597 2.06 1 1.004 3,5-(CF 3 ) 2 C-H C-H C-H N CH 3 CH 2 CO 2 H 583 2.07 1 1.005 3,5-(CF 3 ) 2 C-H C-H C-H C-H C-H N CH 3 CH
  • the invention provides a topical composition comprising at least one isoxazoline of formula (I) in combination at least one other active agent, and a pharmaceutically acceptable carrier or diluent.
  • Additional veterinary/pharmaceutical active ingredients may be used with the compositions of the invention.
  • the additional active agents may include, but are not limited to, acaricides, anthelmintics, anti-parasitics and insecticides.
  • Anti-parasitic agents can include both ectoparasiticidal and/or endoparasiticidal agents.
  • Veterinary pharmaceutical agents that may be included in the compositions of the invention are well-known in the art (see e.g. Plumb' Veterinary Drug Handbook, 5th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005 ) or The Merck Veterinary Manual, 9th Edition, (January 2005 )) and include but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline/theophylline, amiodarone, amitriptyline
  • arylpyrazole compounds such as phenylpyrazoles, known in the art may be combined with the isoxazoline compounds in the topical compositions of the invention.
  • arylpyrazole compounds include but are not limited to those described in U.S. Patent Nos. 6,001,384 ; 6,010,710 ; 6,083,519 ; 6,096,329 ; 6,174,540 ; 6,685,954 and 6,998,131 .
  • one or more macrocyclic lactones or lactams which act as an acaricide, anthelmintic agent and/or insecticide, can be added to the compositions of the invention.
  • the macrocyclic lactones include, but are not limited to, avermectins such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin and ML-1,694,554, and milbemycins such as milbemectin, milbemycin D, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime derivatives of said avermectins and milbemycins. Examples of combinations of arylpyrazole compounds with macrocyclic lactones include but are not limited to those described in U.S. Patent Nos. 6,426,333 ; 6,482,425 ; 6,962,713 and 6,998,131 .
  • the macrocyclic lactone compounds are known in the art and can easily be obtained commercially or through synthesis techniques known in the art. Reference is made to the widely available technical and commercial literature.
  • avermectins ivermectin and abamectin
  • doramectin " Veterinary Parasitology", vol.
  • milbemycins reference may be made, inter alia , to Davies H.G. et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121 , Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336 , U.S. Patent No. 4,134,973 and EP 0 677 054 .
  • Macrocyclic lactones are either natural products or are semi-synthetic derivatives thereof.
  • the structure of the avermectins and milbemycins are closely related, e.g., by sharing a complex 16-membered macrocyclic lactone ring.
  • the natural product avermectins are disclosed in U.S. Patent No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosed in U.S. Patent No. 4,199,569 . Mention is also made of U.S. Patent Nos. 4,468,390 , 5,824,653 , EP 0 007 812 A1 , U.K.
  • Patent Specification 1 390 336 , EP 0 002 916 , and New Zealand Patent No. 237 086 inter alia.
  • Naturally occurring milbemycins are described in U.S. Patent No. 3,950,360 as well as in the various references cited in " The Merck Index” 12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996 ).
  • Latidectin is described in the " International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, vol. 17, no. 4, pp. 263- 286, (2003 ).
  • Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Patent Nos.
  • the invention comprises a topical composition comprising an isoxazoline compound in combination with a class of acaricides or insecticides known as insect growth regulators (IGRs).
  • IGRs insect growth regulators
  • Compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. These compounds all act by interfering with the development or growth of the insect pests.
  • Insect growth regulators are described, for example, in U.S. Patent Nos. 3,748,356 , 3,818,047 , 4,225,598 , 4,798,837 , 4,751,225 , EP 0 179 022 or U.K. 2 140 010 as well as U.S. Patent Nos. 6,096,329 and 6,685,954 .
  • the IGR is a compound that mimics juvenile hormone.
  • juvenile hormone mimics include azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin and 4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.
  • compositions of the invention comprise an isoxazoline compound of formula (I) in combination with methoprene or pyriproxyfen and a pharmaceutically acceptable carrier. It has been surprisingly found that compositions comprising an isoxazoline compound of formula (I) in combination with methoprene or pyriproxyphen exhibit superior long lasting efficacy that is not predictable based on the activity of each active alone.
  • the IGR compound is a chitin synthesis inhibitor.
  • Chitin synthesis inhibitors include chlorofluazuron, cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron, tebufenozide, teflubenzuron, triflumoron, novaluron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.
  • adulticide insecticides and acaricides can also be added to the composition of the invention.
  • pyrethrins which include cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof
  • carbamates including, but are not limited to, benomyl, carbanolate, carbaryl, carbofuran, meththiocarb, metolcarb, promacyl, propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxime and thiofanox.
  • the compositions of the invention may include one or more antinematodal agents including, but not limited to, active agents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines, and organophosphate class of compounds.
  • benzimidazoles including, but not limited to, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and its o,o-dimethyl analogue may be included in the compositions.
  • compositions may include an imidazothiazole compounds including, but not limited to, tetramisole, levamisole and butamisole.
  • compositions of the invention may include tetrahydropyrimidine active agents including, but not limited to, pyrantel, oxantel, and morantel.
  • Suitable organophosphate active agents include, but are not limited to, coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos, mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.
  • the compositions may include the antinematodal compounds phenothiazine and piperazine as the neutral compound or in various salt forms, diethylcarbamazine, phenols such as disophenol, arsenicals such as arsenamide, ethanolamines such as bephenium, thenium closylate, and methyridine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate and dithiazanine iodide; isothiocyanates including bitoscanate, suramin sodium, phthalofyne, and various natural products including, but not limited to, hygromycin B, ⁇ -santonin and kainic acid.
  • compositions of the invention may include antitrematodal agents.
  • Suitable antitrematodal agents include, but are not limited to, the miracils such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenol compounds known in the art including hexachlorophene, bithionol, bithionol sulfoxide and menichlopholan; various salicylanilide compounds including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetolin and emetine.
  • Anticestodal compounds may also be advantageously used in the compositions of the invention including, but not limited to, arecoline in various salt forms, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.
  • compositions of the invention may include other active agents that are effective against arthropod parasites.
  • Suitable active agents include, but are not limited to, bromocyclen, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion,, diemthoate, dioxathion, ethion, famphur, fenitrothion, fenthion, fospirate, iodofenphos, malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel, stirofos, allethrin, cyhalothrin, cypermethrin, deltameth
  • topical compositions of the invention will include permethrin in combination with the isoxazoline active agent.
  • An antiparasitic agent that can be combined with the compound of the invention to form a composition can be a biologically active peptide or protein including, but not limited to, depsipeptides, which act at the neuromuscular junction by stimulating presynaptic receptors belonging to the secretin receptor family resulting in the paralysis and death of parasites.
  • the depsipeptide is emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86 ).
  • compositions of the invention may comprise an active agent from the neonicotinoid class of pesticides.
  • the neonicotinoids bind and inhibit insect specific nicotinic acetylcholine receptors.
  • the neonicotinoid insecticidal agent that can be combined with an isoxazoline compound to form a topical composition of the invention is imidacloprid.
  • Imidacloprid is a well-known neonicotinoid active agent and is the key active ingredient in the topical parasiticide products Advantage®, Advantage® II, K9 Advantix®, and K9 Advantix® II sold by Bayer Animal Health. Agents of this class are described, for example, in U.S. Patent No. 4,742,060 or in EP 0 892 060 .
  • the topical compositions of the invention may comprise nitenpyram, another active agent of the neonicotinoid class of pesticides.
  • Nitenpyram has the following chemical structure and is the active ingredient in the oral product CAPSTARTM Tablets sold by Novartis Animal Health.
  • Nitenpyram is active against adult fleas when given daily as an oral tablet. Nitenpyram works by interfering with normal nerve transmission and leads to the death of the insect. Nitenpyram has a very fast onset of action against fleas. For example, CAPSTARTM Tablets begin to act against fleas in as early as 30 minutes after administration and is indicated for use as often as once a day. However, nitenpyram is only known to be effective when administered orally as a systemic parasiticide, as with CAPSTARTM Tablets.
  • topical compositions of the invention comprising a combination of nitenpyram with an isoxazoline active agent exhibit the very fast onset of action of nitenpyram because this active agent is not known to be active when administered topically.
  • the topical compositions of the invention comprising a combination of a long-lasting isoxazoline active agent with a very fast acting active agent such as the neonicotinoid active agent nitenpyram provide optimal speed of onset and long lasting activity against ectoparasites.
  • Nitenpyram has a very low log octanol-water partition coefficient of -0.64 and a relatively high solubility in water of 840 g/L at 20° C and pH of 7 (see Supplement to Compendium on Continuing Education for the practicing veterinarian, vol. 23, no. 3(a), march 2001 ), indicating that it is not a likely candidate for topical delivery.
  • the effectiveness of topical compositions of the invention that comprise nitenpyram are all the more unexpected in view of the physicochemical properties of the compound.
  • topical compositions comprising at least one isoxazoline compound in combination with an IGR and a neonicotinoid active agent are provided.
  • the invention provides topical compositions comprising an isoxazoline compound of Formula (I) together with an IGR that mimics juvenile hormone and nitenpyram.
  • the invention provides topical spot-on compositions comprising 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide (Compound A) in combination with (S)-methoprene or pyriproxyfen and nitenpyram.
  • topical compositions of the invention provide topical spot-on compositions that comprise 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide (Compound A) in combination with nitenpyram, (S)-methoprene or pyriproxyfen and an avermectin or milbemycin compound.
  • topical compositions comprise 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide (Compound A) in combination with nitenpyram and/or (S)-methoprene or pyriproxyfen and/or an avermectin or milbemycin compound and/or praziquantel.
  • the presence of an avermectin or milbemycin compound and/or praziquantel provides potent activity against endoparasites in addition to activity against ectoparasites.
  • an insecticidal agent that can be combined with the compositions of the invention is a semicarbazone, such as metaflumizone.
  • compositions of the invention may advantageously include a combination of isoxazoline compounds known in the art.
  • active agents are described in WO 2007/079162 , WO 2007/075459 and US 2009/0133319 , WO 2007/070606 and US 2009/0143410 , WO 2009/003075 , WO 2009/002809 , WO 2009/024541 , WO 2005/085216 and US 2007/0066617 and WO 2008/122375 .
  • nodulisporic acid and its derivatives may be added to the compositions of the invention.
  • These compounds are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Patent No. 5,399,582 , 5,962,499 , 6,221,894 and 6,399,786 .
  • the compositions may include one or more of the known nodulisporic acid derivatives in the art, including all stereoisomers, such as those described in the patents cited above.
  • anthelmintic compounds of the amino acetonitrile class (AAD) of compounds such as monepantel (ZOLVIX), and the like may be added to the compositions of the invention.
  • AAD amino acetonitrile class
  • ZOLVIX monepantel
  • the compositions of the invention may also include aryloazol-2-yl cyanoethylamino compounds such as those described in US Patent No. 8,088,801 to Soll et al. , and thioamide derivatives of these compounds, as described in U.S. Patent No. 7,964,621 .
  • compositions of the invention may also be combined with paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61 ; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408 ).
  • the paraherquamide family of compounds is a known class of compounds that include a spirodioxepino indole core with activity against certain parasites (see Tet. Lett. 1981, 22, 135 ; J. Antibiotics 1990, 43, 1380 , and J. Antibiotics 1991, 44, 492 ).
  • marcfortines A-C structurally related marcfortine family of compounds, such as marcfortines A-C, are also known and may be combined with the formulations of the invention (see J. Chem. Soc. - Chem. Comm. 1980, 601 and Tet. Lett. 1981, 22, 1977 ). Further references to the paraherquamide derivatives can be found, for example, in WO 91/09961 , WO 92/22555 , WO 97/03988 , WO 01/076370 , WO 09/004432 , U.S. Patent 5,703,078 and U.S. Patent 5,750,695 .
  • the additional active agent is included in the composition in an amount of between 0.1 ⁇ g and 1000 mg. More typically, the additional active agent may be included in an amount of 10 ⁇ g to 500 mg, 1 mg to 300 mg, 10 mg to 200 mg or 10 mg to 100 mg.
  • the additional active agent may be included in the composition to deliver a dose of 5 ⁇ g/kg to 50 mg/kg per weight of the animal. In other embodiments, the additional active agent may be present in an amount sufficient to deliver a dose of 0.01 mg/kg to 30 mg/kg, 0.1 mg/kg to 20 mg/kg, or 0.1 mg/kg to 10 mg/kg of weight of animal. In other embodiments, the additional active agent may be present in a dose of 5 ⁇ g/kg to 200 ⁇ g/kg or 0.1 mg/kg to 1 mg/kg of weight of animal. In still another embodiment of the invention, the additional active agent is included in a dose between 0.5 mg/kg to 50 mg/kg.
  • compositions of the invention which include at least an isoxazoline active agent and a pharmaceutically acceptable carrier that is suitable for topical application to an animal, have been surprisingly discovered to be stable and effective against a broad spectrum of ectoparasites for an extended period of time.
  • the topical composition will be in the form of a liquid solution or suspension that comprises a pharmaceutically acceptable carrier or diluent that is suitable for application to the skin of an animal.
  • topical, dermal and subdermal formulations including emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on formulations, ready-to-use formulations, spot-on solutions and suspensions.
  • topical compositions of the invention are suitable for topical administration to a localized area of an animal.
  • liquid solution or suspension formulations comprising isoxazoline active agents in a form that can be sprayed on via a metered dose pump or a metered dose aerosol.
  • Isoxazoline active agents such as those of Formula (I) are systemically active such that the ectoparasite is affected when taking a blood meal from the host. Accordingly, a minimum concentration of the compounds in the systemic circulation of the animal is required. However, in some situations the isoxazoline active agent may also be active by contacting the parasite on the surface of the animal.
  • topical application of the inventive compositions can allow for the active agents to be delivered and distributed throughout the hair coat topically and/or may also provide distribution of the active agent via the sebaceous glands of the animals. When the compound is distributed throughout sebaceous glands, the sebaceous glands can act as a reservoir, whereby there can be a long-lasting effect, e.g.
  • Topical application of the inventive compositions enables effective delivery of the active agent transdermally through the skin into the systemic circulation at a concentration sufficient to provide excellent efficacy against ectoparasites.
  • the compositions of the invention achieve distribution of the active agent both topically over the hair coat of the animal and also transdermally into the blood stream.
  • the topical compositions provide a high level of efficacy at unexpectedly low plasma concentrations of the isoxazoline active agent.
  • the outer layer of the epidermis forms the major barrier to both the egress of water and the ingress of xenobiotics into the circulatory system. It is a unique membrane comprised of dead thin flat cells, corneocytes, which are filled with dense keratin, between which is a lipid-rich layer comprised of numerous lipid bilayers. The general consensus is that most xenobiotics pass through the lipid-rich layer between the flat cells. Delivering an active through the skin presents a significant challenge, given the role of the skin as a barrier for keeping foreign substances out. In order for an active ingredient to pass through the stratum corneum, it must pass sequentially across bilayers and therefore cross many hydrophilic-lipophilic interfaces. Because of the efficient barrier of the skin, transdermal delivery is only typically appropriate for potent compounds that require only a small dosage.
  • an active agent to be distributed either topically or transdermally is dependent both on the physicochemical characteristics of the compound and also on the non-active excipients of the formulation, which may induce penetration of the active agent into the skin. While there is no general method to deliver any active agent either topically over the hair coat of an animal or transdermally to an animal, some techniques for enhancing the penetration of active agents into the skin of animals are known. Substances termed “permeation enhancers,” are typically used in compositions designed to deliver drugs transdermally to increase the amount of the active that is delivered into the systemic circulation.
  • Permeation enhancers constitute various classes of compounds including certain solvents such as dimethylsulfoxide (DMSO), pyrrolidones, ethanol, propylene glycol, ethyl acetate, dimethylacetamide, and others that are capable of disrupting the barrier function of the stratum corneum. Other substances have also been shown to increase the flux of certain active agents through the skin. These include lipophilic compounds such as laurocapram (Azone); fatty acids or alcohols such as oleic acid, oleyl alcohol, linoleic acid and the like; certain fatty acid esters such as isopropyl myristate, methyl noanoate, methyl caprate and others.
  • solvents such as dimethylsulfoxide (DMSO), pyrrolidones, ethanol, propylene glycol, ethyl acetate, dimethylacetamide, and others that are capable of disrupting the barrier function of the stratum corneum.
  • Other substances have also been shown to increase the
  • the compositions are formulated to control the rate of permeation of the isoxazoline compound in order to maintain efficacious levels of the active in the plasma for a prolonged period of time and significantly extend the duration of efficacy.
  • the topical compositions of the invention are formulated with a carrier system that induces the containment of the isoxazoline active agent(s) within the skin to achieve a reservoir effect and controls the permeation rate of the compound into the systemic circulation over a longer period of time.
  • the invention provides topical compositions that exhibit surprising long lasting efficacy against ectoparasites. It must be noted that this approach is only applicable to potent active agents that may achieve the desired parasiticidal efficacy with low plasma concentrations, since less potent compounds would not be able to establish an efficacious concentration.
  • topical compositions of the present invention comprising an isoxazoline active agent in a carrier comprising a lipophilic solvent or lipophilic solvent system result in superb efficacy against ectoparasites for an extended duration of time.
  • non-active excipients in certain topical formulations of the invention promote the containment of the isoxazoline active agent within the skin for longer periods of time while allowing the active agent to constantly diffuse into the circulatory system at a rate that provides the required concentration of the active in the blood stream to be efficacious against ectoparasites for a longer period of time.
  • the present invention utilizes non-active excipients that discourage the fast permeation of isoxazoline active agents into the systemic circulation.
  • topical compositions comprising an isoxazoline active agent in a pharmaceutically acceptable carrier wherein the carrier does not include a compound that enhances the permeation of the isoxazoline active agent.
  • topical compositions comprising an isoxazoline active agent and a pharmaceutically acceptable carrier wherein the carrier comprises a solvent or solvent system that promotes the containment of the isoxazoline active agent in the skin of the animal for a longer period of time.
  • the carrier may comprise a solvent selected from carboxylic acid esters, diesters of dicarboxylic acids, fatty acid esters or diesters of fatty diacids, or a combination thereof, including, but not limited to, isopropyl palmitate, isostearyl lactate, diisopropyl adipate, dibutyl adipate, diethyl sebacate, dibutyl sebacate, octyl palmitate, polyethyleneglycol (PEG) stearate and cetearyl octanoate; oils including, but not limited to, mineral oil, diglycerides, triglycerides, jojoba oil, lecithin and castor oil, or a combination thereof; long chain aliphatic alcohols such as isostearyl alcohol and the like; fatty alcohols and their esters, including for example, cetyl alcohol, cetearyl alcohol and the like, or
  • Excipients that may also promote the containment of the active agent in the skin for longer periods of time and may be included in the compositions of the invention include, but are not limited to, mixed esters of sucrose and carboxylic acids including sucrose acetate isobutyrate (SAIB) and the like; low temperature melting waxes, hydrogenated vegetable oils, caprylic/capric glycerides; glycerol esters, including for example, triacetin, glycerol monooleate, glycerol monolinoleate, glycerol stearate, glyceryl distearate and the like; triglycerides, including for example, caprylic, capric/ myristic/ stearic triglyceride; thermoreversible polymers, such as Pluronic and poloxamers, including for example, Lutrol F127 by itself or in mixture with other poloxamers; or a combination thereof.
  • SAIB sucrose acetate isobutyrate
  • the pharmaceutically acceptable carrier for the topical compositions comprises a mixture of a diester of a dicarboxylic acid in combination with one or more of additional solvents listed above, and/or an "oily" lipophilic substance, including a liquid or low melting lipophilic active agent such as (S)-methoprene, pyriproxyfen and/or permethrin; and/or a mixed ester of sucrose and carboxylic acids including a mixed ester of sucrose and acetic and isobutyric acids such as sucrose acetate isobutyrate (SAIB), and/or low melting waxes and/or hard fats.
  • SAIB sucrose acetate isobutyrate
  • the inclusion of certain lipophilic solvents in the topical compositions of the invention promote the residence time of the isoxazoline active agent within the skin while allowing an effective concentration of the active agent to pass slowly into the circulatory system to achieve the desired efficacy for longer periods of time.
  • the diester of a dicarboxylic acid is diethyl sebacate or diisopropyl adipate.
  • the blend of solvents comprising a dicarboxylic acid ester comprises a glycol or polyglycol, or a glycol or polyglycol ether or ester including, but not limited to, ethylene glycol (EG), propylene glycol (PG), liquid polyoxyethylene glycols (PEGs) of various grades including PEG 400, EG or PG monocaprylate, EG or PG caprylate, EG or PG monolaurate, EG or PG dicaprylate/dicaprate, diethyleneglycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl
  • the carrier for the topical compositions comprises a dialkyl ester of a dicarboxylic acid such as diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, dibutyl adipate, or a combination thereof, alone or in combination with solvents selected from:
  • the amount the additional solvents combined with the carboxylic acid ester or diester of a dicarboxylic acid are present in an amount of at least about 1% (v/v), at least 5% (v/v), at least 9.0% (v/v), at least 13% (v/v), at least 17% (v/v) or at least 20% (v/v).
  • the additional solvents will be in an amount of at least 9% (v/v).
  • the additional solvents will be present in an amount of 5-70% (v/v), 10-60% (v/v), 10-50% (v/v), 15-60% (v/v) or 15-50% (v/v). In preferred embodiments, the additional solvents will be present in an amount of 20-70% (v/v), 20-60% (v/v), 20-50% (v/v) or 25-50% (v/v).
  • the pharmaceutically acceptable carrier may include suitable carriers or diluents commonly used in the formulation art including aqueous or organic solvents or mixtures of solvents. These organic solvents may be found, for example, in Remington Pharmaceutical Sciences, 21st Edition (2005 ).
  • Other solvents and/or additives that may be used in the topical compositions include, but are not limited to, PEG ethers and PEG esters including, but not limited to, PEG esters of carboxylic acids and dicarboxylic acids and PEG esters of fatty acids, glycerol esters including triacetin, caprylic/capric triglycerides (Miglyol 812®) and the like; glycerol ethers including glycerol formal; propylene glycol dicaprylate/dicaprate (Miglyol 840®), lauryl lactate, triacetin, diisopropyl adipate (DIPA, also known as CERAPHYL 230), diisobut
  • the invention provides topical compositions comprising at least one isoxazoline active agent, optionally in combination with one or more additional active agents, in a pharmaceutically acceptable carrier, wherein the carrier does not comprise glycofurol.
  • the pharmaceutically acceptable carrier of the topical compositions does not comprise a binary mixture of propylene glycol and glycerol formal.
  • plant oils such as, but not limited to soybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, sunflower oil, etc.
  • mineral oils such as, but not limited to, petrolatum, paraffin, silicone, etc.
  • solvents and/or additives that control the permeation rate of the active may be added to a composition comprising one of the formulation carriers described herein, including carriers comprising a dialkyl ester of a dicarboxylic acid such as diethyl sebacate or the like.
  • solvents and/or additives that control the permeation rate of the active may be added to carriers comprising other solvents described herein or may be used alone in the composition.
  • topical compositions of the invention will utilize solvents that enhance the permeation of the isoxazoline active agent through the skin of the animal rather than solvents and excipients that retain the active agent on the skin of the animal for longer periods of time.
  • topical compositions are provided that include solvents that enhance the permeation of isoxazoline active agents through the skin of the animal.
  • the permeation enhancing solvent permits a greater proportion of the isoxazoline active agent through the skin into the systemic circulation. It will be appreciated by those of skill in the art that this effect allows a greater level of efficacy at lower doses of the active.
  • Selected solvents that enhance the permeation of the isoxazoline active agent include, but are not limited to, dimethyl isosorbide; and glycol ethers including, but not limited to, diethyleneglycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and the like.
  • Other solvents that enhance the permeation of the isoxazoline active agent described below may also be used in the compositions.
  • the pharmaceutically acceptable carrier of the formulation may comprise C 8 -C 20 long-chain aliphatic alcohols or esters thereof.
  • the carrier comprises C 1 -C 12 alcohols or esters thereof, C 1 -C 4 alcohols or esters thereof or C 3 -C 8 alcohols or esters thereof.
  • the esters formed with the alcohol include esters of C 1 -C 12 carboxylic acids or diacids, or esters of C 6 -C 16 carboxylic acids or diacids.
  • Esters include, but are not limited to, acetates such as ethyl acetate and the like; and esters of C 1 -C 12 alcohols and a dicarboxylic acid or a hydroxy-substituted carboxylic acids.
  • the pharmaceutically acceptable carrier comprises C 4 -C 22 fatty acids or esters thereof, including esters with C 6 -C 20 long chain alcohols, C 1 -C 12 alcohols, C 1 -C 4 alcohols or C 3 -C 8 alcohols; C 10 -C 18 saturated fatty acids or esters thereof, including esters with C 6 -C 20 long chain alcohols, C 1 -C 12 alcohols, C 1 -C 4 alcohols or C 3 -C 8 alcohols; C 10 -C 18 unsaturated fatty acids or esters thereof, including esters with C 6 -C 20 long chain alcohols, C 1 -C 12 alcohols, C 1 -C 4 alcohols or C 3 -C 8 alcohols; monoesters or diesters of C 6 -C 16 aliphatic carboxylic acids and carboxylic diacids, including esters with C 6 -C 20 long chain alcohols, C 1 -C 12 alcohols, C 1 -C 4 alcohols or C 3 -C 8 alcohols,
  • compositions of the invention comprise aromatic alcohols or esters thereof.
  • topical compositions of the invention may include benzyl alcohol as a solvent.
  • preferred solvents include C 1 -C 12 alkyl esters of carboxylic acids such as butyl acetate, octyl acetate, lauryl lactate or isopropyl palmitate, and C 1 -C 12 alkyl esters of dicarboxylic acids, including diisopropyl adipate, diethyl sebacate and diisopropyl sebacate.
  • the carrier may include C 1 -C 10 , C 1 -C 8 or C 1 -C 6 alkyl esters of carboxylic acids or C 1 -C 10 , C 1 -C 8 or C 1 -C 6 alkyl diesters or dicarboxylic acids.
  • the carboxylic acid or dicarboxylic acid is a C 4 -C 22 fatty acid or dicarboxylic acid. In another embodiment, the carboxylic acid or dicarboxylic acid is a C 1 -C 12 carboxylic acid or dicarboxylic acid. In other embodiments, the carboxylic acid or dicarboxylic acid is a C 1 -C 10 , C 1 -C 8 or C 1 -C 6 carboxylic acid or dicarboxylic acid.
  • the carrier or diluent include a derivative of glycerol including, but not limited to, glycerol monoesters (e.g. monoglycerides), glycerol diesters (e.g. diglycerides), glycerol triesters (e.g. triglycerides such as triacetin), or glycerol formal, or mixtures thereof.
  • Glycerol formal is a mixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3- dioxolane (approximately 60:40), which are cyclic ether compounds derived from glycerol and having 2 oxygen atoms in the ring structure and substituted by alcohol group.
  • Glycerol Formal is a low odor and low toxic solvent for a wide variety of applications in pharmaceutical and cosmetics industry including anti-parasite veterinary formulations.
  • the organic solvents may comprise diisopropyl adipate, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycol monoethyl ether, triacetin, butyl acetate, benzyl alcohol, octyl acetate, propylene carbonate, oleic acid, or a mixture of at least two of these solvents.
  • the veterinary compositions of the invention comprise a carrier comprising dimethyl isosorbide.
  • Dimethyl isosorbide is a high purity solvent and carrier which offers a safe, effective delivery enhancement mechanism for active ingredients in personal care products and pharmaceutical formulations.
  • dimethyl isosorbide is sometimes used as an epidermal penetration enhancer to provide enhanced penetration of active agents to the epidermis. It may also provide delivery of active agents into the skin while avoiding crystallization of the active agent, which will severely limit the effectiveness of the formulation.
  • Dimethyl Isosorbide is soluble in a variety of ingredients including water, cottonseed oil, isopropanol, isopropyl myristate, propylene glycol, polysorbate 20, and polysorbate 80.
  • the carrier or diluent may comprise a glycol derivative including, but not limited to, propylene glycol, ethylene glycol; glycol ethers and polyglycol ethers including, but not limited to, butyl diglycol, propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, and diethylene glycol monoethyl ether (DGME or Transcutol®).
  • DGME diethylene glycol monoethyl ether
  • the topical compositions of the invention comprising isoxazoline active agent(s) are dissolved in a pharmaceutically acceptable carrier comprising one or more solvents.
  • solvents include, but are not limited to, dimethyl isosorbide (DMI), glycerol formal (methylidinoglycerol or glycerin formal), triacetin, liquid polyethyleneglycols including PEG 400, diisopropyl adipate (DIPA), isopropyl palmitate, silicone fluid including SILICONE FLUID 200 and Silicone Fluid 1cst and /or Silicone Fluid 2cst and the like; propylene glycol (or other aliphatic dihydric alcohols), benzyl alcohol, propylene glycol esters including propylene glycol dicaprylate / dicaprate, propylene carbonate, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate and propylene glycol
  • DMI dimethyl isosorbide
  • the compositions of the invention may include surfactants.
  • the surfactants may be anionic, cationic, non-ionic or amphoteric surfactants.
  • Anionic surfactants include, but are not limited to, alkaline stearates; calcium stearate; triethanolamine stearate; sodium abietate; alkyl sulfates; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, and the like.
  • Examples of cationic surfactant include, but are not limited to, water-soluble quaternary ammonium salts of formula; cetyltrimethylammonium bromide and octadecylamine hydrochloride.
  • Non-ionic surfactants that may be used in the compositions include, but are not limited to, polyoxyethylenated (PEGylated) esters including, but not limited to, sorbitan esters and fatty acid esters; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, and copolymers of ethylene oxide and propylene oxide including, but not limited to, block co-polymers of ethylene oxide and propylene oxide such as poloxamers and the like (e.g.
  • surfactants include, but are not limited to, CAPRYOLTM 90 (propylene glycol monocaprylate), CAPRYOLTM PGMC (propylene glycol monocaprylate) which are oily liquids having an HLB (hydrophilic-lipophilic balance) of 6 and 5, respectively. Topically they can be used as a co-surfactant in microemulsions and as a solubilizer/penetration enhancer.
  • HLB values have the following general meanings: compounds with a HLB value of ⁇ 10 tend to be lipid soluble (water insoluble) and solvents with a HLB > 10 tend to be water soluble.
  • Surfactants having HLB between 4 and 8 are typically useful as anti-foaming agents.
  • Surfactants having HLB from 7 to 11 may be useful as W/O (water in oil) emulsifiers.
  • HLB of 12 to 16 typically indicates a surfactant may be useful in oil in water emulsions, and HLB of 11 to 14 is indicative of a wetting agent.
  • HLB of 12 to 15 is typical of detergents, and HLB of 16 to 20 indicates a solubilizer or hydrotrope.
  • HLB value alone cannot be used to predict whether a particular surfactant will serve a specific purpose (e.g. anti-foaming agent, emulsifier, wetting agent, solubilizer, hydrotrope). Therefore, in general, determination of a suitable system of solvent, active agent, surfactant(s) and other excipients necessarily involves non-routine experimentation and inventive effort.
  • compositions may also include surfactants such as oleoyl macrogolglycerides (polyoxylglycerides, for example, LABRAFIL ® M1944CS and LABRAFIL ® M2125CS both having an HLB of 4). These compounds may also be used, for example, as oily phase for emulsions, microemulsions, and as penetration enhancers.
  • surfactants such as oleoyl macrogolglycerides (polyoxylglycerides, for example, LABRAFIL ® M1944CS and LABRAFIL ® M2125CS both having an HLB of 4).
  • oleoyl macrogolglycerides polyoxylglycerides, for example, LABRAFIL ® M1944CS and LABRAFIL ® M2125CS both having an HLB of 4
  • These compounds may also be used, for example, as oily phase for emulsions, microemulsions, and as penetration enhancers.
  • the polyoxylglycerides may include polyethyleneglycol caprylic/caprylic glycerides such as LABRASOL® (HLB of 14. Topically it is used as a surfactant in microemulsions, and can also act as a solubility/penetration enhancer in topical formulations.
  • LABRASOL® HLB of 14. Topically it is used as a surfactant in microemulsions, and can also act as a solubility/penetration enhancer in topical formulations.
  • the surfactant is LAUROGLYCOLTM90 (propylene glycol monolaurate) having an HLB of 5. It is a co-surfactant for microemulsions in topical formulations and can also act as a solubilizer/penetration enhancer in topical formulations.
  • the surfactant is PLUROL® OLEIQUE CC497 (polyglyceryl oleate), having an HLB of 6.
  • solvents suitable for topical formulations may be characterized as having good spreading properties while other solvents for topical formulations may be characterized by an ability to enhance permeation of active agents through the skin barrier into the systemic circulation (see for example, Pharmaceutical Skin Penetration Enhancement, edited by Jonathan Hadgraft and Kenneth A. Walters, Marcel Dekker, Inc. New York 1993 ).
  • solvents suitable for topical formulations may include both good spreading and good permeation characteristics.
  • DIPA, diisopropyl sebacate, DES and Miglyol 840 have both good spreading and permeation characteristics.
  • Transcutol, DMI, lauryl lactate, propylene glycol caprylate, propylene glycol monocaprylate and propylene glycol monolaurate have good permeation enhancing properties but are not considered to have particularly good spreading properties.
  • the compositions will comprise mixtures of solvents that will enhance the spreading ability and/or the permeation enhancing ability of the composition.
  • formulations are provided wherein the carrier comprises solvents that exhibit both good spreading and permeation characteristics including, but not limited to, DIPA, diisopropyl sebacate, DES and Miglyol® 840.
  • the invention provides formulations wherein the carrier comprises solvents that exhibit good spreading characteristics.
  • formulations are provided wherein the carrier vehicle comprises solvents that enhance the permeation of the active agent through the skin into the systemic circulation.
  • the composition exhibits long lasting efficacy and provides protection against parasites in domestic animals for at least one month.
  • the composition comprises a carrier that includes a solvent system comprised of a carboxylic acid alkyl ester or diester of a dicarboxylic acid.
  • the composition comprises a blend of solvents comprising a carboxylic acid alkyl ester or a diester of a dicarboxylic acid.
  • compositions of the invention exhibit very long lasting efficacy of at least 90% against fleas and/or ticks that for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months against fleas and/or ticks.
  • the long-lasting composition comprises a carrier that includes a carboxylic acid alkyl ester or a diester of a dicarboxylic acid, including diethyl sebacate and diisopropyl adipate.
  • the long-lasting composition comprises a carboxylic acid alkyl ester or a diester of a dicarboxylic acid combined with an co-solvent including, but not limited to, a propylene glycol (PG) ester including PG monocaprylate, PG caprylate, PG monolaurate and PG dicaprylate/dicaprate; diethyleneglycol monoethyl ether (DGME, Transcutol®), mineral oil, triglycerides, diglycerides, isostearyl alcohol, isostearyl lactate, dibutyl adipate, dibutyl sebacate; polyethylene glycols (PEGs) including PEG 400, PEG stearate; lecithin, castor oil and castor oil derivatives, film formers, myristyl myristate, dimethiconol argenine, sucrose acetyl isobutyrate, and the like, or a combination thereof.
  • PG propylene glycol
  • the long-lasting compositions that provide an efficacy of at least 90% against fleas and/or ticks for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months, comprise a carrier vehicle that includes dimethyl isosorbide.
  • DMI is a known permeation enhancer, and use of this solvent in some topical formulations of the invention results in increased delivery of the active agent into the systemic circulation.
  • the long-lasting compositions that provide an efficacy of at least 90% against fleas and/or ticks comprises a glycol ether including, but not limited to, diethyleneglycol monoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and the like.
  • DGME diethyleneglycol monoethyl ether
  • Transcutol® diethyleneglycol monoethyl ether
  • butyl diglycol dipropylene glycol n-butyl ether
  • dipropylene glycol n-butyl ether ethyleneglycol monoethyl ether
  • dipropylene glycol monomethyl ether dipropylene glycol monomethyl ether
  • isoxazoline active agents such as those of Formula (I), and in particular 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide (Compound A), are systemically active such that the ectoparasite is affected when taking a blood meal from the host. Accordingly, a minimum concentration of the compounds in the systemic circulation of the animal is required to effectively control ectoparasites such as ticks and fleas.
  • topical formulations of the invention comprising an isoxazoline active agent provide excellent efficacy against fleas and ticks at unexpectedly very low plasma concentrations.
  • topical compositions of the invention comprising selected solvents and excipients, including dialkyl esters of dicarboxylic acids such as diethyl sebacate and the like, result in constant low levels of the active agent over a prolonged period of time.
  • concentration of the active agent in the plasma that is sufficient to obtain at least 90% efficacy against fleas and/or ticks is less than or equal to 200 ng/mL or less than or equal to 150 ng/mL.
  • the concentration of the isoxazoline active agent in the plasma required to attain 90% efficacy against fleas and/or ticks is less than or equal to 100 ng/mL, less than or equal to 75 ng/mL or even less than or equal to 50 ng/mL. In other embodiments of the invention, the concentration of the isoxazoline active agent in the plasma required to attain 90% efficacy against fleas and ticks is 75-100 ng/mL, 50-75 ng/mL or 30-50 ng/mL.
  • the concentration of the isoxazoline active agent (Compound A) in the plasma required to attain an efficacy of at least 90% against certain tick species compared to an untreated control or a control group treated with a placebo was significantly less than the plasma concentration required to attain 90% efficacy from another mode of administration that achieves high systemic exposure, such as oral or injectable administration. It was found that the concentration of the isoxazoline active agent required to achieve 90% efficacy against the tick species A . americanum, D. variabilis and R. sanguineus in dogs was 42%, 36% and 32% lower than the concentration required from oral administration (see Example 13).
  • the lower plasma concentration required to achieve 90% efficacy from the topical compositions of the invention may indicate that the compositions provide protection against ectoparasites by acting both topically on the surface of the animal and systemically.
  • the improved efficacy of the topical compositions of the invention against these tick species at significantly lower plasma concentrations may allow for a longer duration of efficacy based on the ability of the non-active excipients in the inventive compositions to provide a slow delivery of effective amounts of isoxazoline active agents into the blood stream from the site of application.
  • the addition of certain other active agents with the isoxazoline active agent in the topical compositions of the invention significantly enhanced the long lasting efficacy of the compositions.
  • inclusion of an IGR active agent such as the juvenile hormone mimic methoprene in the topical compositions resulted in significantly longer lasting efficacy against ectoparasites.
  • the invention provides very long lasting topical compositions comprising at least one isoxazoline active agent in combination with an insect growth regulator (IGR) active agent.
  • IGR insect growth regulator
  • the IGR will be a juvenile hormone mimic including azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene, pyriproxyfen, tetrahydroazadirachtin or 4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin-3(2H)-one, as discussed herein. More preferably, the IGR will be methoprene or pyriproxyfen. As described in the non-limiting examples, the inclusion of the IGR (S)-methoprene with the isoxazoline active agent resulted in significantly longer lasting efficacy. This effect is surprising and unexpected, as methoprene is not an adulticide (see Examples 1-3).
  • a topical composition comprising nitenpyram in combination with an isoxazoline active agent and optionally an IGR active agent and/or other oily active agents and/or active agents with low melting points such as permethrin, provide efficacy of at least 90% against fleas as early as 12 hours after administration of the topical formulation and also provide long lasting efficacy.
  • the topical compositions provide efficacy of at least 90% against fleas as early as 9 hours or 6 hours after administration.
  • the compositions comprising a combination of nitenpyram and an isoxazoline active agent provide efficacy of at least 90% against fleas as early as 12 hours, 9 hours or 6 hours after treatment and an efficacy of at least 90% for a period of at least 1 month.
  • the compositions comprising a combination of nitenpyram and an isoxazoline active agent provide efficacy of at least 90% as early as 12 hours, 9 hours or 6 hours after treatment and an efficacy of at least 90% for a period of at least 2 months or at least 3 months, or longer.
  • compositions of the invention may be in the form of oil-in-water or water-in-oil emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
  • Suitable emulsifying agents include naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan mono oleate, and the like.
  • the emulsions may also contain preservatives.
  • the composition of the invention is in the form of a microemulsion.
  • Microemulsions are well suited as the liquid carrier vehicle. Microemulsions are typically quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a co-surfactant. They are usually translucent and isotropic liquids. Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is typically less than 200 nm (1000 to 100,000 nm for emulsions).
  • the interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
  • SA surface-active
  • Co-SA co-surface-active
  • the oily phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds.
  • the oily phase comprises of triglycerides.
  • the triglycerides are medium-chain triglycerides, for example C 8 -C 10 caprylic/capric triglyceride.
  • the oily phase will represent a % v/v range selected from the group consisting of 1 to 20%; 2 to 15%; 7 to 10%; and 8 to 9% v/v of the microemulsion.
  • the aqueous phase typically includes, for example water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycols or glycerol.
  • the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof.
  • the aqueous phase will represent a proportion from 1 to 10% v/v or 1 to 4% v/v in the microemulsion.
  • Surfactants for the microemulsion typically include diethylene glycol monoethyl ether, dipropyelene glycol monomethyl ether, polyglycolyzed C 8 -C 10 glycerides or polyglyceryl-6 dioleate, or a combination of these surfactants.
  • the co-surfactants include short-chain alcohols, such as ethanol and propanol.
  • poloxamers and Pluronic F127 can be used as surfactants.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin, and the like.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol, and the like. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid or other known preservatives.
  • Aqueous suspensions may contain the active agents in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide, with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • Colorants may be added to the inventive formulations.
  • Colorants contemplated by the present invention are those commonly known in the art. Specific colorants include, for example, dyes, FD&C Blue #1 Aluminum Lake, caramel, colorant based upon iron oxide or a mixture of any of the foregoing. Especially preferred are organic dyes and titanium dioxide. Preferred ranges include from 0.01% to 2% (w/v), more preferably from 0.01% to 0.5% (w/v).
  • compositions of the invention are in the form of a spot-on formulation that is applied to a localized area on an animal, rather than the entire coat of the animal or a large portion of the animal's coat. In one embodiment of a localized region, the location is between the shoulders.
  • the spot-on formulation according to the present invention provide long-lasting and broad-spectrum efficacy against ectoparasites and/or endoparasites when the solution is applied to the animal.
  • the spot-on formulations provide for topical administration of a concentrated solution, suspension, microemulsion or emulsion for intermittent application to localized area on the animal, generally between the two shoulders.
  • Spot-on formulations are well known techniques for topically delivering certain antiparasitic agents to a limited area of the host. However, not all compounds are suited for formulation in spot-on formulations because the physicochemical characteristics of the active agent may not allow effective distribution of the compound topically or transdermally.
  • U.S. Patent Nos. 5,045,536 , 6,395,765 ; 6,096,329 ; 7,262,214 ; 6,426,333 ; 6,482,425 ; 6,962,713 ; 6,998,131 ; and 7,531,186 describe spot-on formulations.
  • WO 01/957715 describes a method for controlling ectoparasites in small rodents as well as interrupting or preventing the diseases caused by arthropods in small rodents, which comprise applying topical formulations, such as spot-on compositions, to the skin, or hair of the rodents.
  • Spot-on formulations may be prepared by dissolving the active ingredients into the pharmaceutically or veterinary acceptable vehicle.
  • the spot-on formulation can be prepared by encapsulation of the active ingredients to leave a film of the therapeutic agent on the surface of the animal.
  • These formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.
  • the pharmaceutically acceptable carrier may be a liquid carrier vehicle as described herein, and other carriers described in the art, for example in U.S. Patent No. 6,395,765 and other patents listed in the previous paragraph.
  • the liquid carrier vehicle can optionally contain a crystallization inhibitor such as the crystallization inhibitors described below, or mixtures thereof, to inhibit the formation of crystals or precipitate of the active components.
  • the veterinarily acceptable carrier will generally comprise a diluent or vehicle in which the active agents are soluble. It will be apparent to those of skill in the art that the carrier or diluent of the topical compositions must be able to deliver the active agents to the targeted location without the active agents precipitating from solution or forming crystals. In some embodiments, the carrier or diluent of the compositions will be suitable to avoid precipitation or crystallization of the active agents. In other embodiments, the compositions may include a crystallization inhibitor component in addition to the carrier or diluent.
  • Crystallization inhibitors which are useful for the invention include but are not limited to:
  • a crystallization inhibitor pair will be used. Such pairs include, for example, the combination of a film-forming agent of polymeric type and of a surface-active agent. Other crystallization inhibitor pairs include a polyethylene glycol and a non-ionic surfactant. Additional crystallization pairs including other mixtures are also contemplated. These agents can be selected from the compounds mentioned above as crystallization inhibitor.
  • the agents are of the polymeric type which include but are not limited to the various grades of polyvinylpyrrolidone, polyvinyl alcohols, polyethylene glycols and copolymers of vinyl acetate and of vinylpyrrolidone.
  • the agents include but are not limited to those made of non-ionic surfactants.
  • the agent is a polyoxyethylenated ester of sorbitan.
  • the agents include the various grades of polysorbate, for example Polysorbate 80 and polyoxyethylenated derivatives of castor oil including hydrogenated castor oil derivatives.
  • the film-forming agent and the surface-active agent can be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned above.
  • the crystallization inhibitor can be present in a proportion of 1 to 30% (w/v). Typically, the crystallization inhibitor may be present in a proportion of 1% to 20% (w/v), 1% to 10% (w/v), or 5% to 15% (w/v). Acceptable inhibitors are those whose addition to the formulation inhibits the formation of crystals of the active agents when the formulation is applied. In some embodiments, formulations may include compounds that function as crystallization inhibitors other than those listed herein.
  • the suitability of a crystallization inhibitor may be determined by testing if it will sufficiently inhibit the formation of crystals so that a sample containing 10% (w/v) of the isoxazoline active agent in a solvent as described above with 10% (w/v) of the crystallization inhibitor will result in less than 20, preferably less than 10 crystals when placed on a glass slide at 20° C for 24 hours.
  • an emollient and/or spreading and/or film-forming agent may be added to the topical compositions of the invention.
  • Emollients, spreading agents and film forming agents are well known in the art.
  • the emollients, spreading agents and film forming agents that may be used in the topical compositions include the components listed in (a) to (g) above, including polymer derivatives such as polyvinylpyrrolidone, polyvinyl alcohols and copolymers of vinyl acetate and vinylpyrrolidone; anionic surfactants; cationic surfactants; non-ionic surfactants; amphoteric surfactants; amine salts, and combinations thereof.
  • the emollient is used in a proportion of from 0.1 to 10%, or 0.25 to 5% (w/v).
  • a fragrance may be added to any of the compositions of the invention.
  • Fragrances which are useful for the invention include but are not limited to:
  • the inventive formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the formulation art. Antioxidants such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene), BHA and citric acid, monothioglycerol, tert-butyl hydroquinone (TBHQ), and the like, may be added to the present formulation.
  • the antioxidants are generally added to the formulation in amounts of from 0.01 to 2.0%, based upon total weight of the formulation, with 0.05 to 1.0% being especially preferred.
  • Preservatives such as the parabens (methylparaben and/or propylparaben), are suitably used in the formulation in amounts ranging from 0.01 to 2.0%, with 0.05 to 1.0% being especially preferred.
  • Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Preferred ranges for these compounds include from 0.01 to 5%.
  • Buffering systems include, for example, systems selected from the group consisting of acetic acid/acetate, malic acid/malate, citric acid/citrate, tartaric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate.
  • pour-on formulations are described, for example, in U.S. Patent No. 6,010,710 .
  • Some pour-on formulations are advantageously oily, and generally comprise a diluent or vehicle and also a solvent (e.g. an organic solvent) for the active ingredient if the latter is not soluble in the diluent.
  • Other pour-on formulations may be in hydrophilic carriers, including in alcohol, glycol or glycol ether based carriers.
  • Pour-on formulations are typically administered to livestock animals such as cattle and sheep.
  • pour-on formulations are administered to the animal as a stripe to an external surface of the animal, e.g. a stripe from head to tail of the animal.
  • the process may comprise applying the solution to livestock animals before they arrive in the Feed Lot, it being possible for this application to be the final one before the animals are slaughtered.
  • the isoxazoline(s) active agents are present in the formulation at a concentration of 1 to 25% (w/v). In some embodiments of the invention, the isoxazoline active agents are present in the formulation as a concentration from 1 to 20% (w/v), 1 to 10% (w/v), 5 to 15% (w/v), or 5 to 10% (w/v). In other embodiments, the isoxazoline active agent(s) are present in the compositions at a concentration of 1 to 5% (w/v), 3-6 % (w/v) or 0.5% to 2.0% (w/v).
  • the volume of the topical composition applied is not restricted as long as the amount of substance administered is practical and shown to be safe and effective. Typically, the volume applied depends on the size and weight of the animal as well as the concentration of active, the extent of infestation by parasites and the type of administration. For spot-on compositions, the volume applied is typically of the order of 0.1 ml to 10 ml, 0.1 ml to 5 ml, or 0.1 to 1 ml, or, or. In other embodiments, the volume may be 4 ml to 7 ml. For larger animals, the volume may be higher including, but not limited to, up to 10 ml, up to 20 ml or higher.
  • the volume is on the order of about 0.5 ml to 1 ml or 0.5 ml to 2 ml for cats, and on the order of 0.3 to 3 ml or 4 ml for dogs, depending on the weight of the animal.
  • the volume applied can be of the order of 0.3 to 100 mL.
  • the volume applied of the pour-on formulations may be 1 ml to 100 ml or 1 ml to 50 ml.
  • the volume may be 5 ml to 50 ml or 10 ml to 100 ml.
  • Dosage forms may contain from 0.5 mg to 5 g of a combination of active agents. More typically, the amount of active is present in an amount of from 1 mg to 500 mg of an active agent, 1 mg to 100 mg or 1 mg to 25 mg. In still other embodiments, the amount of the active agent present in the compositions is 10 mg 50 mg or 10 mg to 100 mg. In other embodiments, the amount of active agent present in the compositions is 50 mg to 200 mg, 100 mg to 300 mg, 100 mg to 400 mg, 200 mg to 500 mg, 300 mg to 600 mg, 400 mg to 800 mg, or 500 mg to 1000 mg.
  • compositions of the invention are made by mixing the appropriate amount of the active agents, pharmaceutically acceptable carrier or diluent and optionally a crystallization inhibitor, antioxidant, preservative, film former, etc., to form a composition of the invention.
  • the composition can be obtained by following the method of making these forms described above by the description of making these forms found in general formulation text known to those in the art, e.g. Remington - The Science and Practice of Pharmacy (21st Edition) (2005 ), Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th Edition) (2005 ) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8th Edition), edited by Allen et al., Lippincott Williams & Wilkins, (2005 ).
  • compositions or formulations of the invention have long-lasting efficacy against ectoparasites (e.g. fleas and ticks) and in certain embodiments may also active against endoparasites that harm animals.
  • compositions of the invention are effective include, but are not limited to, fleas, ticks, mites, mosquitoes, flies and lice.
  • the compositions of the invention may also be effective against endoparasites including, but not limited to, cestodes, nematodes, hookworms and roundworms of the digestive tract of animals and humans.
  • the ectoparasite is one or more insect or arachnid including those of the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Ambylomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola.
  • the ectoparasite is from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and/or Boophilus.
  • the ectoparasites treated include but are not limited to fleas, ticks, mites, mosquitoes, flies, lice, blowfly and combinations thereof. Specific examples include, but are not limited to, cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp. and the like), ticks ( Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyoma sp.
  • ectoparasites include but are not limited to the tick genus Boophilus, especially those of the species microplus (cattle tick), decoloratus and annulatus; myiases such as Dermatobia hominis (known as Berne in Brazil) and Cochliomyia hominivorax (greenbottle); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa).
  • Flies proper namely those whose adult constitutes the parasite, such as Haematobia irritans (horn fly) and Stomoxys calcitrans (stable fly); lice such as Linognathus vituli, etc.; and mites such as Sarcoptes scabiei and Psoroptes ovis.
  • Haematobia irritans horn fly
  • Stomoxys calcitrans stable fly
  • lice such as Linognathus vituli, etc.
  • mites such as Sarcoptes scabiei and Psoroptes ovis.
  • the above list is not exhaustive and other ectoparasites are well known in the art to be harmful to animals and humans. These include, for example migrating dipterous larvae.
  • the composition can also be used to treat against endoparasites such as those helminths selected from the group consisting of Anaplocephala, Ancylostoma, Anecator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostumum, Ostertagia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, and Trichostrongylus, among others.
  • endoparasites such as those helminths selected from the group consisting of Anaplocephala, Ancylostoma, Anecator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostumum, Ostertagia, Toxocara, Strongyloides, Tox
  • Disclosed herein are methods for the treatment and prevention of parasitic infections and infestations of animals including livestock and companion animals such as cats, dogs, horses, birds including chickens, sheep, goats, pigs, turkeys and cattle, with the aim of ridding these hosts of parasites commonly encountered by such animals.
  • the invention provides compositions for the treatment or prevention of parasitic infections and infestations in companion animals including, but not limited to, cats and dogs.
  • the compositions are particularly effective for preventing or treating parasitic infestations of cats and dogs with fleas and ticks.
  • the compositions of the invention are for use in the treatment or prevention of parasitic infections and infestations in cattle or sheep.
  • the compositions are particularly effective against Rhipicephalus (Boophilus) microplus, Haematobia irritans (horn fly), Stomoxys calcitrans (stable fly), and sheep myiases such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa).
  • treating or “treat” or “treatment” are intended to mean the application or administration of a composition of the invention to an animal that has a parasitic infestation for the eradication of the parasite or the reduction of the number of the parasites infesting the animal undergoing treatment. It is noted that the compositions of the invention may be used to prevent such a parasitic infestation.
  • compositions of the invention are administered in parasiticidally effective amounts which are which are suitable to control the parasite in question to the desired extent, as described below.
  • the compounds and compositions of the invention can be applied against a single pest or combinations thereof.
  • compositions of the invention may be administered continuously, for treatment or prevention of parasitic infections or infestations.
  • the compositions of the invention deliver an effective amount of the active compounds to the animal in need thereof to control the target parasites.
  • effective amount is intended a sufficient amount of a composition of the invention to eradicate or reduce the number of parasites infesting the animal.
  • an effective amount of the active agent achieves at least 70% efficacy against the target parasite.
  • an effective amount of the active agent achieves at least 80%, or at least 90% efficacy against the target pests.
  • an effective amount of the active agent will achieve at least 95%, at least 98% or 100% efficacy against the target parasites.
  • a dose of from 0.001 to 100 mg per kg of body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but, of course, there can be instances where higher or lower dosage ranges are indicated, and such are within the scope of this invention. It is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific host and parasite.
  • the dose of the isoxazoline active agent administered from the topical compositions of the invention is between 0.1 to 30 mg per kg of body weight. More typically the dose of the isoxazoline active agent administered is 0.5 to 20 mg/kg or 0.5 to 15 mg/kg body weight. Preferably, the dose of the isoxazoline active agent administered is 0.5 to 10 mg/kg, 0.5 to 8 mg/kg or 0.5 to 5 mg/kg of body weight.
  • the dose of the isoxazoline active agent administered will be 0.5 to 2 mg/kg of body weight, preferably 1 mg/kg of bodyweight. In other embodiments for the very long lasting treatment and protection of cats against parasitic infestations or infections a dose of 2 to 15 mg/kg of bodyweight or preferably 5 to 15 mg/kg of bodyweight will be administered.
  • a dose of 2 to 15 mg/kg of bodyweight of the isoxazoline active agent will be administered. In other embodiments, a dose of 2 to 8 mg/kg or 2 to 5 mg/kg of bodyweight will be administered.
  • doses of the isoxazoline active agent administered may be 1 to 30 mg/kg of body weight. More typically the doses administered will be 1 to 20 mg/kg or 1 to 15 mg/kg. Preferably, a dose of the isoxazoline active agent administered to livestock animals will be 1 to 10 mg/kg of body weight.
  • the amount of active agents for birds and other animals which are small in size is greater than 0.01 mg/kg, and in another embodiment for the treatment of small-sized birds and other animals, the amount of is between 0.01 and 20 mg/kg of weight of animal. More typically the dose of the isoxazoline for small-sized animals and birds is 0.5 to 15 mg/kg, 0.5 to 10 mg/kg of body weight, or 0.5 mg/kg to 5 mg/kg of body weight.
  • a composition comprising an isoxazoline compound has an efficacy against fleas and/or ticks of at least 90.0% or higher for 1 month, or longer.
  • the compositions of the invention provide an efficacy against fleas and/or ticks of at least 95.0% or higher for 30 days, or longer.
  • topical compositions of the invention provide an efficacy against fleas and/or ticks in cats and dogs of at least 80% for two months, or longer. In another embodiment, the topical compositions provide efficacy against fleas and/or ticks in cats and dogs of 90% for two months, or longer. In still another embodiment, the compositions provide an efficacy of 95% for 2 months or longer.
  • the composition has an efficacy of at least 80% against fleas and/or ticks for 3 months, or longer.
  • the topical compositions of the invention provide an efficacy of at least 90% against fleas and/or ticks for 3 months or longer.
  • the topical compositions of the invention provide an efficacy of at least 95% against fleas and/or ticks for 3 months or longer.
  • the topical compositions of the invention provide an efficacy against fleas and/or ticks in cats and/or dogs of at least 80% or at least 90% for 3 months to 6 months or longer.
  • the topical spot-on compositions of the invention are administered to the animal over a localized region of the animal, e.g. between the two shoulders.
  • the localized region has a surface area of 10 cm 2 or larger.
  • the localized region has a surface area of between 5 and 10 cm 2 , or smaller.
  • pour-on topical compositions described herein may be administered in a line along the back of the animal approximately between the shoulders and the hind quarters.
  • solutions according to the invention may be applied using any means known per se, e.g. using an applicator gun or a metering flask, pipette, syringes, roll on, droppers, capsules, foil packages, vials, twist tip containers, metered-dose aerosols or sprays and other single dose and multi-dose containers.
  • kits for the treatment or prevention of a parasitic infestation in an animal which comprises at least one isoxazoline active agent together with a pharmaceutically acceptable carrier and a dispensing device for topical application of the composition.
  • the dispensing device may be a pipette, syringes, roll on, droppers, capsules, foil packages, vials, twist tip containers, metered-dose aerosols or sprays and other single dose and multi-dose containers, which includes an effective dose of each active agent in the pharmaceutically acceptable carrier or diluent.
  • An important aspect of the invention is to provide a multiple-use container comprising a topical composition of the invention, from which accurate single dose aliquots of the long lasting topical formulations may be administered.
  • the formulation must remain stable with repetitive exposure to the outside environment, particularly oxygen and water.
  • This embodiment may be particularly useful with the very long lasting formulations of the invention that require administration to an animal infrequently, such as once every 3-6 months, or similar.
  • Some solvents such as ethers (including DMI, Transcutol® and the like) give rise to peroxides, which then yield ketones and aldehydes that may be further degraded to acids. The presence of acids may contribute to the degradation of acid hydrolysis-susceptible molecules, including isoxazoline active agents.
  • formulation stability is particularly important for the multi-dose container application, where the formulations can be exposed to oxygen and water during multiple rounds of opening and closing.
  • certain antioxidants described herein including BHT and BHA, efficiently inhibit the degradation of the active agent in ether solvents.
  • a 12% (w/v) solution of Compound A in DMI exhibited no significant change in assay over the course of an eleven week accelerated stability study at 50 °C in clear glass containers.
  • antioxidants such as vitamin E, alpha tocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene), BHA and citric acid, monothioglycerol and the like, may be added to the topical compositions to inhibit the formation of oxidative species.
  • the antioxidants are generally added to the formulation in amounts of from 0.01 to 2.0%, based upon total weight of the formulation, with 0.05 to 1.0% being especially preferred.
  • Liquid vehicles suitable for topical isoxazoline-containing formulations for control of parasites were investigated.
  • Formulations comprising an isoxazoline compound in combination with one or more additional active agents, including (S)-methoprene, pyriproxyfen and nitenpyram, were also prepared and tested.
  • Formulations were prepared with a variety of liquid carrier vehicles and evaluated for effectiveness to control ectoparasites, particularly fleas and ticks in cats and dogs, and ticks, mites and lice in cattle.
  • Solvent systems comprising either one solvent, including a diester of a dicarboxylic acid and/or an ether such as dimethyl isosorbide, or a combination of solvents including a diester of a dicarboxylic acid, specifically diethyl sebacate, and at least a second solvent(s) are encompassed by the invention.
  • formulations comprising a single solvent such as DES or DMI or a combination of solvents were investigated.
  • Solvents combined with a diester of a dicarboxylic acid include, but are not limited to: 1) a propylene glycol ester or ether, including PG monocaprylate, PG caprylate, PG monolaurate, PG dicaprylate/dicaprate, PG caprylic/capric triglycerides (LABRASOL®) or a combination thereof; 2) an ether (e.g.
  • dimethyl isosorbide dimethyl isosorbide
  • second ester triacetin, lauryl lactate
  • a fatty acid ester including, but not limited to, isopropyl palmitate, isostearyl lactate, dibutyl adipate, dibutyl sebacate, octyl palmitate, polyethyleneglycol stearate and cetearyl octanoate
  • 5) a glycol or polyglycol ether such as Transcutol®, PEG 400 and the like
  • an oil such as mineral oil, diglycerides, triglycerides, jojoba oil, lecithin and castor oil
  • 7) a long chain aliphatic alcohol such as isostearyl alcohol
  • mixed esters sucrose and carboxylic acids including sucrose acetate isobutyrate (SAIB) and the like.
  • topical compositions of the invention comprise Transcutol®, glycerol formal, triacetin, propylene carbonate, benzyl alcohol or DMI.
  • Non-limiting formulations comprising an isoxazoline compound (Cmpd. A) alone or in combination with the non-limiting additional active agents (S)-methoprene, pyriproxyfen and nitenpyram are provided in below. * Denotes formulation falling outside the scope of the claimed invention. * Formulation 1 - Add diethyleneglycol monoethyl ether (Transcutol®) (50% of volume required); Polysorbate 80 and Ethanol are added; the BHA, BHT, povidone 17, and Cmpd. A are then added and mixed until dissolved, and the mixture is QS with Transcutol®. Ingredients Function % Cmpd.
  • Transcutol® diethyleneglycol monoethyl ether
  • DIPA diisopropyl adipate
  • A dissolve; add (S)-methoprene; QS DES.
  • Ingredients Function % Cmpd A Active 6.0 w/v (S)-methoprene Active 9.0 w/v Propylene glycol monolaurate Permeation enhancer 25.0 v/v DES Spreading agent QS * Formulation 5 - Add DES (50% of required volume); add PG monocaprylate; add Cmpd.
  • A dissolve; add (S)-methoprene; QS DES.
  • A dissolve; add (S)-methoprene; QS DES Ingredients Function % Cmpd.
  • A dissolve; add nitenpyram, dissolve; add (S)-methoprene and dissolve; QS with DMI.
  • Ingredients Function % Cmpd A Active 0.5-2 w/v Nitenpyram Active 2-8 w/v (S)-methoprene Active 7-10 w/v Dimethyl isosorbide Solvent QS Formulation 29 - Add DMI (50% of required volume), add Cmpd.
  • A dissolve; add nitenpyram, dissolve; add pyriproxyfen and dissolve; QS DMI.
  • Ingredients Function % Cmpd Ingredients Function % Cmpd.
  • A dissolve; add nitenpyram, dissolve; add pyriproxyfen and dissolve; QS GF.
  • Ingredients Function % Cmpd A Active 0.5-2 w/v Nitenpyram Active 2-8 w/v pyriproxyfen Active 3-6 w/v Glycerol formal Solvent QS * Formulation 32 - Add triacetin (50% of required volume), add Cmpd.
  • A dissolve; add nitenpyram, dissolve; add pyriproxyfen and dissolve; QS triacetin.
  • Ingredients Function % Cmpd Ingredients Function % Cmpd.
  • Example 1 Efficacy of a Spot-on Composition Comprising a Combination of Cmpd. A and (S)-methoprene Against Dermacentor variabilis Ticks and Ctenocephalides felis Fleas in Dogs
  • Dogs in Group 1 were untreated (control). Dogs in Groups 2, 3 and 4 were treated topically with spot-on compositions comprising 3.7% (w/v) Cmpd. A and 9% (w/v) (S)-methoprene administered to deliver 2.5 mg/kg Cmpd. A and 6 mg/kg (S)-methoprene (Group 2: Transcutol with 10% (w/v) ethanol, 5% (w/v) TWEEN 80 and 5% (w/v) polyvinylpyrrolidone; Group 3: DMI and glycerol formal (GF); and Group 4: DIPA). All dogs were treated once on Day 0.
  • Plasma samples were collected from all dogs in the study on Days -6, 0 (at 4 h and 12 h), 1, 2, 9, 16, 23, 30, 36, 44, 51, 58, 64, 72, 79 and 86. Plasma samples were analyzed for the concentration of Compound A using an LC/MS/MS analytical method that was GLP validated for the purpose.
  • Percent reduction (also referred as efficacy) against fleas was 100% through and including Day 30 for all treatment groups (see Table 1). Percent reduction against fleas was above 95% through Day 58 for Group 3.
  • the percent reduction against ticks was >94% through and including Day 23 (48 hours infestation, see Table 2). Percent reduction was >92% for Groups 6 and 7 on Day 30.
  • Example 2 Efficacy of Spot-on Formulations Containing Compound A and (S)-methoprene Against Ctenocephalides felis.
  • Example 2 Following the initial studies described in Example 1, additional topical formulations comprising Compound A in combination with an insect growth regulator, ( S )-methoprene, in carrier vehicles comprising both a spreading solvent and a permeation solvent were studied. Thus, the efficacy of five different topical formulations comprising Compound A and ( S )-methoprene against the cat flea ( Ctenocephalides felis) in dogs was determined using to a protocol similar to that of Example 1.
  • Dogs in Group 1 were untreated, and served as a control group. Dogs in Groups 2-6 were treated topically with formulations comprising Cmpd.
  • a + (S)-methoprene administered at 6 mg/kg Group 2: Miglyol 840; Group 3: DIPA / 25% triacetin; Group 4: DIPA / 25% DMI; Group 5 DIPA / 25% ethyl hexyl pelargonate; and Group 6: DIPA + 25% diisopropyl sebacate + 3% silicone fluid).
  • Dogs in Group 7 were treated at a dose level of 7.0 mg/kg Compound A + (S)-methoprene at 6 mg/kg with a formulation comprising DIPA + 25% diisopropyl sebacate + 3% silicone fluid.
  • the concentrations of Compound A and (S)-methoprene in formulations of Groups 2-5 were 6.0% (w/v) and 9.0% (w/v), respectively, and the concentration of Compound A and (S)-methoprene in formulations of Groups 6 and 7 were 10.5% (w/v) and 9% (w/v), respectively.
  • Dogs were infested with approximately 100 C. felis fleas on Day -1. Dogs were treated with the respective topical formulations on Day 0. Fleas were removed and counted on Day 2. Infestations with about 100 fleas were also made on Days 8, 15, 22, 29, 36 and 43. Fleas were combed and counted 24 ⁇ 3 hours after infestation on Days 9, 16, 23, 30, 37 and 44.
  • Table 3 below provides the % efficacy for each of the topical formulations. As demonstrated by the data, each of the formulations was highly efficacious against the cat flea through at least 44 days. Table 3: Efficacy of Spot-on Composition Against Ctenocephalides felis Treatment Group Geometric Mean Flea Count / % Reduction Day 2 Day 9 Day 16 Day 23 Day 30 Day 37 Day 44 Group 2 % Reduction 100.0 100.0 100.0 100.0 100.0 100.0 100.0 98.6 Group 3 % Reduction 100.0 99.6 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Group 4 % Reduction 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Group 5 % Reduction 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Group 6 % Reduction 99.6 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0
  • Example 3 Efficacy of Spot-on Formulations Containing Compound A and ( S )-Methoprene Against Rhipicephalus Sanguineus.
  • Dogs in Group 1 were untreated, and served as a control group. Dogs in Groups 2-6 were treated topically with Cmpd.
  • Dogs in Group 7 were treated at a dose level of 7.0 mg/kg Compound A + (S)-methoprene at 6 mg/kg with a formulation comprising DES / 25% propylene glycol monolaurate.
  • the concentrations of Compound A and (S)-methoprene in the formulations used with Groups 2-6 were 6.0% (w/v) and 9.0% (w/v), respectively.
  • the concentrations of Compound A and (S)-methoprene in the formulation used with Group 7 were 10.5% (w/v) and 9% (w/v), respectively.
  • Treatment Groups 1, 5, 6 and 7 only were infested on Days 70, 77 and 84, and Treatment Groups 1, 6 and 7 only on Day 91.
  • Ticks were counted upon removal on Days 2, 9, 16, 23, 30, 37, 44, 51, 58 and 65. Tick counts were conducted for Treatment Groups 1, 5, 6 and 7 only on Days 72, 79 and 86 and Treatment Groups 1, 6 and 7 only on Day 93.
  • Tables 4A and 4B below presents the efficacy of the spot-on formulations administered to Groups 2-7 against R. sanguineus.
  • Table 4A Efficacy Against Rhipicephalus Sanguineus in Dogs Treatment Group % Reduction Ticks Day 2 Day 9 Day 16 Day 23 Day 30 Day 37 Day 44 Group 2 % Reduction 96.9 100.0 100.0 100.0 100.0 98.6 Group 3 % Reduction 94.5 100.0 100.0 100.0 94.5 97.9 97.7 Group 4 % Reduction 98.2 100.0 100.0 100.0 97.5 94.5 98.6 Group 5 % Reduction 98.2 100.0 100.0 98.1 100.0 97.9 100.0 Group 6 % Reduction 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Group 7 % Reduction 96.9 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Table
  • Groups 3 and 4 maintained at least a 90% reduction in tick count through Day 51, Groups 2 and 5 through Day 58, and Groups 6 and 7 through Day 79.
  • Treatment Groups 6 and 7 demonstrated superior efficacy for an extended period of time.
  • formulations comprising a combination of an isoxazoline and an insect growth regulator in a carrier vehicle comprising a combination of a spreading solvent and a permeation enhancer were determined to provide surprisingly long lasting efficacy against R. sanguineus.
  • the efficacy of a spot-on composition comprising an isoxazoline compound (Cmpd. A) in a carrier vehicle comprising either DES alone or DES + lauryl lactate (LL), against ticks ( Amblyomma americanum ) , in dogs was studied.
  • the compositions contained 3.0 %, 4.5%, or 6.0% Cmpd.
  • a to dogs infested with A . Americanum ticks.
  • Treatment Group 1 was administered a placebo formulation and served as a control.
  • Treatment Groups 2, 3 and 4 were administered a topical formulation comprising 6.0% (w/v), 4.5% (w/v) and 3.0% (w/v) of Cmpd.
  • a in DES respectively, corresponding to doses of 4.0 mg/kg, 3.0 mg/kg and 2.0 mg/kg, respectively.
  • Treatment Groups 5, 6 and 7 were administered a topical formulation comprising 6.0% (w/v), 4.5% (w/v) and 3.0% (w/v) of Cmpd.
  • a in DES + 9% lauryl lactate respectively, corresponding to doses of 4.0% mg/kg, 3.0 mg/kg and 2.0 mg/kg body weight Cmpd. A, respectively.
  • All dogs were treated once topically on Day 0 by parting the hair and applying the solution from a syringe directly onto the skin in a single spot on the midline of the neck between the base of the skull and the shoulder blades.
  • Plasma samples were collected from all dogs on Days -5, 0 (at 4 h and 12 h), 1, 2, 9, 16, 23, 30, 37 and 44. Plasma samples were analyzed for the concentration of Compound A using a LC/MS/MS method that was GLP validated for the analysis of the compound.
  • Treatment Groups 5 and 6 (4.0 mg/kg and 3.0 mg/kg Cmpd. A in DES + LL, respectively) maintained at least 90% efficacy through five weeks, and Treatment Group 2 (4.0 mg/kg in DES alone) maintained at least 90% efficacy through Week 3.
  • Treatment Group 1 was a placebo control and received 0.067 mL/kg of body weight.
  • Treatment Group 2 was administered a topical spot-on formulation comprising 6.0% (w/v) Cmpd.
  • Treatment Group 3 was administered a topical spot-on formulation comprising 12% (w/v) Cmpd.
  • Table 6A Efficacy Against Ctenocephalides felis in Dogs - Day 0 to Day 22 Treatment Group Day 1 Day 8 Day 15 Day 22 Group 2 % Reduction 100.0 100.0 100.0 100.0 Group 3 % Reduction 100.0 100.0 100.0 100.0 Table 6B: Efficacy against Ctenocephalides felis in Dogs - Day 28 to Day 43 Treatment Group Day 29 Day 36 Day 43 Group 2 % Reduction 100.0 100.0 99.2 Group 3 % Reduction 100.0 100.0 100.0 100.0 100.0
  • Table 7 The percent efficacy against ticks is presented in Table 7. Both Treatment Groups demonstrated good efficacy at least through 31 days. Table 7: Efficacy against Rhipicephalus sanguineus Ticks Treatment Group Day 2 Day 30 Day 31 Day 38 Control Group 2 % Reduction 100.0 91.5 100.0 85.2 Group 3 % Reduction 100.0 72.6 100.0 51.3
  • Example 6 Efficacy of Spot-on Formulations Comprising Compound A at Different Doses against Rhipicephalus sanguineus Ticks in Dogs
  • Treatment Group 1 dogs were treated with a placebo solution.
  • Treatment Group 2 was treated with a formulation comprising 6% (w/v) Cmpd. A in DES;
  • Treatment Group 3 were treated with a composition comprising 6% (w/v) Cmpd. A in 40% DES/DMI;
  • Treatment Group 4 were treated with a formulation comprising 6% (w/v) Cmpd. A in DES with 30% Capryol 90. All dogs were treated once topically on Day 0.
  • Topical solutions were applied by parting the hair and applying the solution from a syringe directly onto the skin in a single spot on the midline of the neck between the base of the skull and the shoulder blades.
  • the percent efficacies of the treated groups compared to the untreated control group were determined for the 48 hour post-treatment/infestation counts. Percent efficacy for each counting time 48 hours after treatment or infestation are listed in Table 8. Treatment Group 3 maintained ⁇ 90% efficacy 48 hours after infestation at every sampling time from Day 9 through Day 44. Treatment Group 2 was able to maintain at least 90% efficacy 48 hours after infestation throughout the six weeks of the study.
  • Table 8 Efficacy Against Rhipicephalus sanguineus in Dogs Treatment Group Day 2 Day 9 Day 16 Day 23 Day 30 Day 37 Day 44 Group 2 % Reduction 93.2 100.0 100.0 100.0 97.8 95.3 97.5 Group 3 % Reduction 72.8 100.0 100.0 100.0 100.0 93.5 82.9 Group 4 % Reduction 97.2 100.0 100.0 100.0 98.4 96.1 78.1
  • Example 7 Efficacy of Spot-on Formulations Comprising Isoxazoline Compound A in Different Carrier Vehicles at 1 mg/kg against Ctenocephalides felis Fleas in Cats
  • Cats were infested with approximately 100 C. felis on Day -1 and treated on Day 0 with the corresponding spot-on formulation by application of the formulation directly on the skin in the midline of the neck, between the base of the skull and the shoulder blades in a single spot using a 1 mL syringe. Twelve hours after treatment, fleas were removed and counted. The cats were immediately re-infested with approximately 100 fleas.
  • Example 8 Efficacy of Spot-on Formulations Comprising Isoxazoline Compound A in Different Carrier Vehicles at 1 mg/kg against Ctenocephalides felis Fleas in Cats Protected from Grooming.
  • Each cat in the study was fitted with a protective neck collar on Day -1 prior to treatment to prevent the animals from orally ingesting the topically applied formulation while grooming.
  • Cats were infested with approximately 100 C. felis on Day -1 and treated on Day 0 with the corresponding spot-on formulation by application of the formulation directly on the skin in the midline of the neck, between the base of the skull and the shoulder blades in a single spot using a 1 mL syringe.
  • Infestations with approximately 100 C. felis were conducted weekly on Days 7, 14, 21, 28 and 35.
  • Fleas were removed and counted approximately 24 ⁇ 3 hours following treatment on Day 1 and then on Days 8, 15, 22, 29 and 36.
  • the efficacy for each formulation is presented in Table 10 below.
  • Example 9 Long lasting Efficacy of Spot-on Composition Against Ctenocephalides felis Fleas in Cats.
  • Cats in all treatment groups were infested on Days -1, 0 (approx. 12 h following treatment), 7, 28, 49, 70, 91, 105, 119 and 133. Cats were also infested on Days 126 and 140 (Treatment Groups 1 and 2); Days 147, 154, 155, 161, 168 and 175 (Treatment Groups 1, 3 and 4); Days 182, 189 and 197 (Treatment Groups 1 and 4). After each infestation, fleas were removed and counted approximately 48 hours ( ⁇ 3 hours) for most time points.
  • Table 11A Efficacy of Against Ctenocephalides felis Fleas in Cats Treatment Group % Reduction Fleas Day 0 (12 hr) Day 2 Day 9 Day 30 Day 51 Day 72 Day 93 Group 2 % Reduction 61.1 100.0 100.0 100.0 100.0 100.0 100.0 Group 3 % Reduction 95.4 100.0 100.0 100.0 100.0 100.0 Group 4 % Reduction 85.3 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Table 11B: Efficacy of against Ctenocephalides felis Fleas in Cats (continued) Treatment Group % Reduction Fleas Day 107 Day 121 Day 128 Day 135 Day 142 Day 149 Day 155 Group 2 % Reduction 100.0 92.3 89.1 88.3 80.0 ND ND Group 3 % Reduction 100.0 100.0 ND 99.8 ND 99.5 50.0 Group 4 % Reduction 100.0 100.0 ND 100.0 ND 100.0 78.0 Table 11 C: Mean Flea Count
  • Table 12A Efficacy Against Ixodes ricinus in Cats Treatment Group % Reduction Ticks Day 2 Day 9 Day 23 Day 30 Day 37 Day 44 Group 2 % Reduction 23.71 100.00 99.60 100.00 99.58 100.00 Group 3 % Reduction 70.27 100.00 100.00 100.00 100.00 100.00 100.00
  • Cats were allocated into five Treatment Groups with 5 cats per group: Group 1 - cats were untreated (control); Group 2 - cats were treated spot-on solution containing 0.83% (w/v) Compound A, 2.08% (w/v) nitenpyram, and 4.17% (w/v) pyriproxyfen in Transcutol® to deliver doses of 1.0 mg/kg Compound A, 2.5 mg/kg nitenpyram and 5.0 mg/kg pyriproxyfen; Group 3 - cats were treated a spot-on solution containing 0.83% (w/v) Compound A, 4.17% (w/v) nitenpyram, and 4.17% (w/v) pyriproxyfen in Transcutol® to deliver doses of 1.0 mg/kg Compound A, 5.0 mg/kg nitenpyram and 5.0 mg/kg pyriproxyfen; Group 4 - cats were treated with a spot-on composition containing 0.83% (w/v) Compound A, 8.3
  • Table 13 Efficacy of Spot-on Formulation Comprising Three Active Agents against Ctenocephalides felis Fleas in Cats Treatment Group % Reduction Day 0 (12 h) Day 1 (24 h) Day 2 (24 h) Day 8 (24 h) Day 15 (24 h) Day 22 (24 h) Group 2 % Reduction 99.17 100.00 100.00 100.00 100.00 98.76 % Group 3 99 59 9922 99 78 100 00 99.51 97.71 Group 4 % Reduction 97.69 100.00 100.00 100.00 100.00 98.08 Group 5 % Reduction 99.44 99.79 100.00 100.00 96.76 93.63
  • Example 12 Efficacy of Spot-on Compositions Comprising Compound A against Otodectes cynotis (ear mites) in Cats.
  • Cats in Groups 2 and 3 were treated once on Day 0 with a spot-on composition comprising Compound A at two different concentrations and doses by application of the formulation directly on the skin in the midline of the neck between the base of the skull and the shoulder blades with a 1 mL disposable syringe.
  • Cats in Group 2 were treated with a spot-on composition containing 5.0% (w/v) Compound A in a carrier containing 40% (v/v) diethyl sebacate (DES) in dimethylisosorbide (DMI) at a dose of 5 mg/kg body weight; and cats in Group 3 were treated with a spot-on composition containing 10.0% (w/v) Compound A in a carrier containing 40% (v/v) DES in DMI at a dose of 10 mg/kg body weight.
  • Assessment of the ear mite infestation by otoscopic examination was performed on all cats on Days -7, 3, 7 and 14. Visible live ear mites (adult or immature) were counted and debris/cerumen level was estimated for both ear ducts.
  • Example 13 Efficacious Plasma Concentration for Topical Compositions.
  • Plasma concentrations of Compound A from dogs in the studies of Examples 1 and 4 were determined according to the description in Example 1, and the plasma concentration versus % efficacy against A . americanum and D. variabilis were fit to a Sigmoidal Emax model.
  • the EC 90 (concentration required to achieve 90% efficacy) against A . americanum and D. variabilis ticks were determined to be 92 ng/mL and 70 ng/mL, respectively.
  • the EC 90 for R. sanguineus ticks from a separate study was found to be 69 ng/mL.
  • sanguineus ticks was found to be 158 ng/mL, 110 ng/mL and 101 ng/mL, respectively. Since Compound A is systemically active, the lower concentration of the compound in the plasma required to achieve 90% efficacy from the topical compositions of the invention is surprising and unexpected.
  • the efficacy of a pour-on formulation comprising isoxazoline Compound A was tested and compared with an untreated control.
  • Two healthy, female Angus crossbread cattle of one year of age weighing between 224 to 330 kg were used in each study group.
  • Cattle in Group 1 were untreated (control) and cattle in Group 2 were treated with a pour-on formulation comprising Compound A at a concentration of 10% (w/v) in DES at a dose of 1 ml/10 kg once on Day 0.
  • the formulation was applied by measuring the required amount of the solution into a marked disposable syringe and applying the material evenly along the mid-line of the back of each animal from the withers to the tail head.
  • Table 14A Efficacy of Pour-on Formulation against Horn Fly Treatment Group 1 % Reduction Day 1 (5 h) Day 2 (24 h) Day 7 (5 h) Day 8 (24 h) Day 14 (5 h) Day 15 (24 h) Group 2 % Reduction 81.2 99.6 84.2 99.7 89.5 99.2
  • Table 14B Efficacy of Pour-on Formulation against Horn Fly (Continued) Treatment Group 1 % Reduction Day 21 (5 h) Day 22 (24 h) Day 28 (5 h) Day 29 (24 h) Day 35 (5 h) Day 36 (24 h) Group 2 % Reduction 67.6 97.4 11.7 90.4 42.6 90.4
  • cattle are infested three times a week with approximately 2500 Rhipicephalus (Boophilus) microplus larvae to establish ongoing infestations.
  • Cattle in Groups 2 and 3 were treated with the respective compositions on Day 0 by measuring the required amount of the solution into a marked disposable syringe and applying the material evenly along the mid-line of the back of each animal from the withers to the tail head.
  • Each animal was challenged by infestation with approximately 5000 R. microplus larvae on Days 7 and 21 and every 14 days thereafter. Ticks dropping from each animal in the previous 24 hours were collected daily and counted from Day 1 until the end of the study. Since the life cycle of the ticks from the point of infestation with larvae until engorged ticks fall off is approximately 21 days (average), the assessment of efficacy for the challenges on Days 7 and 21 and every 14 days thereafter, was done for a range of 7 or 8 days starting approximately 21 days after the challenge. The assessment of efficacy at the beginning of the study was done from day 1 until Day 21.
  • Tables 15A and 15B below shows the total tick count % efficacy of the two pour-on formulations against R. microplus through 139 days post treatment compared with an untreated control group.
  • Tables 16A and 16B show the % efficacy of the two pour-on formulations based on the weight of the ticks collected.
  • Figures 2 and 3 shows plots of the % efficacy of the two formulations based on total tick counts and total weight, respectively.
  • the pour-on formulations at both 2.5 mg/kg and 10 mg/kg provide excellent efficacy against Rhipicephalus (Boophilus) microplus ticks for an extended period of time.
  • the pour-on compositions exhibited tick count efficacy above 90% for at least day 139 after administration of the composition.
  • the two pour-on compositions were extremely effective against ticks based on the weight of the ticks collected. This data shows that the compositions were highly effective at inhibiting the reproductive capability of the ticks for an extended duration of time.
  • the extremely long lasting efficacy above 90% for pour-on composition against Rhipicephalus (Boophilus) microplus ticks is remarkable compared with pour-on formulations known in the art.
  • Table 15A Tick Count Efficacy Against Rhipicephalus (Boophilus) microplus Treatment Group Average % Efficacy (Tick Count) Day 1-21 Day 28-34 Day 41-48 Day 55-62 Day 69-76 Day 83-90 Day 97-104 Challenge Day 7 21 35 49 63 77 Group 2 % Efficacy 58.8 75.6 77.0 91.2 88.3 90.7 79.8 Group 3 % Efficacy 78.1 92.0 98.0 97.8 99.3 98.9 92.4
  • Table 15B Tick Count Efficacy against Rhipicephalus (Boophilus) microplus Treatment Group Average % Efficacy (Tick Count) Day 111-118 Day 132-139 Day 146-153 Day 160-167 Challenge Day 91 112 126 140 Group 2 % Efficacy 79.0 86.2 30.3 74.0 Group 3 % Efficacy 96.6 92.4 72.4 85.8 Table 16A: Tick Weight Efficacy against
  • Cattle in Group 2 were treated on Day 0 with a pour-on formulation comprising Compound A at a concentration of 2.5% (w/v) in DES at a dose of 2.5 mg/kg; and cattle in Group 3 were treated on Day 0 with a pour-on formulation comprising Compound A at a concentration of 10% (w/v) in DES at a dose of 10 mg/kg.
  • the formulation was applied by measuring the required amount of the solution into a marked disposable syringe and applying the material evenly along the mid-line of the back of each animal from the withers to the tail head.
  • Live lice (adults plus nymphs) were counted on days 2, 7, 14, 21, 28, 35, 42, 49 and 56 by counting lice on six selected sites approximately 5 cm x 15 cm on the body surface of the animal by direct examination. In the absence of lice on the selected sites, a thorough body search was conducted. The total louse counts per animal were determined by summation of the live louse numbers at each site per animal.
  • Tables 17A and 17B below show the efficacy of the two pour-on formulations against Linognathus vituli over 56 days. As the tables show, both pour-on formulations were efficacious through at least day 56 of the study with 100% efficacy observed starting day 7. Efficacy on day 2 of the study was greater than 90% in each of the study groups.
  • Table 17A Efficacy of Pour-on Formulation Against Linognathus vituli Treatment Group 1 % Reduction Day 2 Day 7 Day 14 Day 21 Day 28 Group 2 % Reduction 92 100 100 100 100 Group 3 % Reduction 98 100 100 100 100 100
  • Table 17B Efficacy of Pour-on Formulation against Linognathus vituli (continued) Treatment Group % Reduction Day 35 Day 42 Day 49 Day 56 Group 2 % Reduction 92 100 100 100 Group 3 % Reduction 98 100 100 100 100 100
  • Cattle in Group 2 were treated on Day 0 with a pour-on formulation comprising Compound A at a concentration of 2.5% (w/v) in DES at a dose of 2.5 mg/kg; and cattle in Group 3 were treated on Day 0 with a pour-on formulation comprising Compound A at a concentration of 10% (w/v) in DES at a dose of 10 mg/kg.
  • the formulation was applied by measuring the required amount of the solution into a marked disposable syringe and applying the material evenly along the mid-line of the back of each animal from the withers to the tail head.
  • compositions of the invention comprising at least one isoxazoline active agent show superior long lasting efficacy against ectoparasites in a mammal (e.g. dogs, cats and cattle).

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PL16187099T PL3172964T3 (pl) 2011-09-12 2012-09-12 Kompozycje przeciwpasożytniczne zawierające izoksazolinową substancję czynną, sposób i ich zastosowania
SI201231857T SI3172964T1 (sl) 2011-09-12 2012-09-12 Sestavki proti parazitom, ki obsegajo izoksazolinsko aktivno sredstvo, postopek in njihove uporabe
EP20190542.9A EP3788874A1 (en) 2011-09-12 2012-09-12 Parasiticidal compositions comprising an isoxazoline active agent, method and uses thereof
RS20201351A RS61048B1 (sr) 2011-09-12 2012-09-12 Paraziticidne kompozicije koje sadrže izoksazolin aktivni agens, postupak i njihove primene
HRP20201745TT HRP20201745T1 (hr) 2011-09-12 2020-10-29 Paraziticidni pripravci koji sadrže djelatno sredstvo izoksazolina, postupak za njih i njihove uporabe
CY2021015C CY2021015I1 (el) 2011-09-12 2021-06-24 Παρασιτοκτονες συνθεσεις οι οποιες περιλαμβανουν εναν δραστικο παραγοντα ισοξαζολινης, μεθοδος και χρησεις αυτων
HUS2100024C HUS2100024I1 (hu) 2011-09-12 2021-06-25 Izoxazolint tartalmazó parazita-ellenes készítmények, ezek elõállítása és alkalmazása

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Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2507210B (en) 2011-07-13 2020-09-02 Clarke Mosquito Control Products Inc Insecticidal compositions and methods of using the same
EP3788874A1 (en) * 2011-09-12 2021-03-10 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal compositions comprising an isoxazoline active agent, method and uses thereof
ME03323B (me) 2012-02-06 2019-10-20 Merial Inc Paraziticidne oralne veterinarske kompozicije koje sadrže sistemski djelujuća aktivna sredstva, metodi i primjene istih
JP6088637B2 (ja) 2012-04-04 2017-03-01 インターベット インターナショナル ベー． フェー． イソオキサゾリン化合物のための固形経口医薬組成物
WO2014141223A1 (en) 2013-03-15 2014-09-18 Argenta Manufacturing Limited Chewable formulation
NZ719916A (en) * 2013-11-01 2017-09-29 Merial Inc Antiparasitic and pesticidal isoxazoline compounds
MX2016008118A (es) * 2013-12-20 2016-09-16 Intervet Int Bv Composiciones de isoxazolina y uso de las mismas en la prevencion o tratamiento de infestaciones parasitarias en animales.
CN105979944A (zh) 2013-12-20 2016-09-28 英特维特国际股份有限公司 异噁唑啉衍生物用于治疗或预防家禽中的节肢动物侵袭的用途
GB2523811A (en) * 2014-03-06 2015-09-09 Norbrook Lab Ltd Novel Isoxazolines and their uses
CN104095871A (zh) * 2014-07-10 2014-10-15 青岛蔚蓝生物股份有限公司 一种含盐酸林可霉素与硫酸大观霉素的兽用注射液
AU2015371175B2 (en) * 2014-12-22 2021-03-04 Intervet International B.V. Use of isoxazoline compounds for treating demodicosis
AU2016214467B2 (en) * 2015-02-03 2020-01-16 Bimeda Finance S.A.R.L. A formulation for treatment of blowfly strike
UY36570A (es) * 2015-02-26 2016-10-31 Merial Inc Formulaciones inyectables de acción prolongada que comprenden un agente activo isoxazolina, métodos y usos de las mismas
JP6824900B2 (ja) 2015-04-08 2021-02-03 ベーリンガー インゲルハイム アニマル ヘルス ユーエスエイ インコーポレイテッド イソオキサゾリン活性薬剤を含む延長放出注射製剤、方法及びその使用
JP6933983B2 (ja) * 2015-06-23 2021-09-08 インターベット インターナショナル ベー． フェー． 衛生化飲料水と共に使用するためのビタミンｅを含有するイソオキサゾリン溶液
UY37137A (es) 2016-02-24 2017-09-29 Merial Inc Compuestos antiparasitarios de isoxazolina, formulaciones inyectables de acción prolongada que los comprenden, métodos y usos de los mismos
CN109071283B (zh) * 2016-04-26 2022-03-04 奥加诺株式会社 水处理剂组合物及水处理方法
US20170333305A1 (en) * 2016-05-23 2017-11-23 Microban Products Company Topical skin product having retention property
WO2018039508A1 (en) 2016-08-25 2018-03-01 Merial, Inc. Method for reducing unwanted effects in parasiticidal treatments
EP3525590A1 (en) 2016-10-14 2019-08-21 Boehringer Ingelheim Animal Health USA Inc. Pesticidal and parasiticidal vinyl isoxazoline compounds
MX2019009685A (es) 2017-02-13 2019-10-07 Clarke Mosquito Control Products Inc Composicion insecticida.
UA125727C2 (uk) * 2017-04-05 2022-05-25 Бьорінґер Інґельхайм Енімал Хелт Юесей Інк. Кристалічні форми (s)-афоксоланеру
US10420109B2 (en) * 2017-04-13 2019-09-17 Futurewei Technologies, Inc. System and method for providing explicit feedback in communications systems with multi-point connectivity
CN111194316A (zh) 2017-08-14 2020-05-22 勃林格殷格翰动物保健美国公司 农药的和杀寄生物的吡唑-异噁唑啉化合物
PL3723739T3 (pl) * 2017-12-15 2024-09-16 Tarsus Pharmaceuticals, Inc. Preparaty izoksazolinowe i ich zastosowanie w leczeniu zapalenia powiek
AR113997A1 (es) 2017-12-21 2020-07-08 Intervet Int Bv Composiciones antiparasitarias para unción dorsal continua
RU2676326C1 (ru) * 2017-12-26 2018-12-28 Федеральное государственное бюджетное научное учреждение "Прикаспийский зональный научно-исследовательский ветеринарный институт" Комплексная антибактериально-противогельминтозная композиция для лечения сельскохозяйственных животных и птиц
TWI812673B (zh) * 2018-02-12 2023-08-21 美商富曼西公司 用於防治無脊椎害蟲之萘異噁唑啉化合物
GB201809374D0 (en) * 2018-06-07 2018-07-25 Fish Vet Group Norge As Treatment for removing ectoparasites from fish
AU2020290958A1 (en) * 2019-06-14 2022-02-03 Piedmont Animal Health Inc. Long-acting topical formulation and method of use thereof
AU2021278871A1 (en) 2020-05-28 2023-01-19 Boehringer Ingelheim Animal Health USA Inc. Bi-modal release intra-ruminal capsule device and methods of use thereof
WO2022118814A1 (ja) * 2020-12-01 2022-06-09 住友化学株式会社 液体農薬組成物
CA3205997A1 (en) 2020-12-21 2022-06-30 University Of Georgia Research Foundation Inc. Parasiticidal collar comprising isoxazoline compounds
CN112755049A (zh) * 2021-02-05 2021-05-07 哈密市动物疫病预防控制中心 用于提高犬绦虫病粪便检测灵敏度的泻剂配方及制备方法
CN114042065B (zh) * 2021-11-26 2024-03-15 长沙拜特生物科技研究所有限公司 一种复方甲苯咪唑透皮溶液剂及其制备方法
WO2023167248A1 (ja) * 2022-03-01 2023-09-07 国立研究開発法人産業技術総合研究所 害虫の呼吸器形成機構を標的とする新規害虫防除方法
WO2023183831A1 (en) * 2022-03-22 2023-09-28 Equilibre Biopharmaceuticals Bv Liquid formulations of ivermectin compositions and use in gelatin dosage forms

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040213744A1 (en) * 1999-05-20 2004-10-28 U & I Pharmaceuticals Ltd. Topical spray compositions

Family Cites Families (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL160809C (nl) 1970-05-15 1979-12-17 Duphar Int Res Werkwijze ter bereiding van benzoylureumverbindingen, alsmede werkwijze ter bereiding van insekticide prepara- ten op basis van benzoylureumverbindingen.
JPS4914624A (es) 1972-06-08 1974-02-08
US3950360A (en) 1972-06-08 1976-04-13 Sankyo Company Limited Antibiotic substances
US3818047A (en) 1972-08-07 1974-06-18 C Henrick Substituted pyrones
SE434277B (sv) 1976-04-19 1984-07-16 Merck & Co Inc Sett att framstella nya antihelmintiskt verkande foreningar genom odling av streptomyces avermitilis
CH604517A5 (es) 1976-08-19 1978-09-15 Ciba Geigy Ag
US4134973A (en) 1977-04-11 1979-01-16 Merck & Co., Inc. Carbohydrate derivatives of milbemycin and processes therefor
US4199569A (en) 1977-10-03 1980-04-22 Merck & Co., Inc. Selective hydrogenation products of C-076 compounds and derivatives thereof
US4144352A (en) 1977-12-19 1979-03-13 Merck & Co., Inc. Milbemycin compounds as anthelmintic agents
US4203976A (en) 1978-08-02 1980-05-20 Merck & Co., Inc. Sugar derivatives of C-076 compounds
JPS57139012A (en) 1981-02-23 1982-08-27 Sankyo Co Ltd Anthelmintic composition
US4427663A (en) 1982-03-16 1984-01-24 Merck & Co., Inc. 4"-Keto-and 4"-amino-4"-deoxy avermectin compounds and substituted amino derivatives thereof
JPS59199673A (ja) 1983-04-25 1984-11-12 Sumitomo Chem Co Ltd 含窒素複素環化合物、その製造法およびそれを有効成分とする有害生物防除剤
IL76708A (en) 1984-10-18 1990-01-18 Ciba Geigy Ag Substituted n-benzoyl-n'-(2,5-dichloro-4(1,1,2,3,3,3-hexafluoropropyloxy)-phenyl)ureas,their preparation and pesticidal compositions containing them
DE3681465D1 (es) 1985-02-04 1991-10-24 Nihon Bayer Agrochem K.K., Tokio/Tokyo, Jp
DE3603799A1 (de) 1986-02-07 1987-08-13 Philips Patentverwaltung Stromspiegelschaltung
EP0237482A1 (de) 1986-03-06 1987-09-16 Ciba-Geigy Ag C(29)-Carbonyloxi-milbemycin-Derivate zur Bekämpfung von tier- und pflanzenparasitären Schädlingen
RU2024527C1 (ru) 1986-03-25 1994-12-15 Санкио Компани Лимитед Способ получения макролидных соединений
GB8613914D0 (en) 1986-06-07 1986-07-09 Coopers Animal Health Liquid formulations
ES2039258T3 (es) 1986-07-02 1993-09-16 Ciba-Geigy Ag Pesticidas.
US4855317A (en) 1987-03-06 1989-08-08 Ciba-Geigy Corporation Insecticides and parasiticides
US4871719A (en) 1987-03-24 1989-10-03 Ciba-Geigy Corporation Composition for controlling parasites in productive livestock
US4874749A (en) 1987-07-31 1989-10-17 Merck & Co., Inc. 4"-Deoxy-4-N-methylamino avermectin Bla/Blb
DE3888936T2 (de) 1987-11-03 1994-07-21 Beecham Group Plc Zwischenprodukte für die Herstellung makrolider Antibiotika mit anthelmintischer Wirkung.
NZ232422A (en) 1989-02-16 1992-11-25 Merck & Co Inc 13-ketal milbemycin derivatives and parasiticides
IE904606A1 (en) 1989-12-21 1991-07-03 Beecham Group Plc Novel products
NZ247278A (en) 1991-02-12 1995-03-28 Ancare Distributors Veterinary anthelmintic drench comprising a suspension of praziquantel in a liquid carrier
WO1992022555A1 (en) 1991-06-17 1992-12-23 Beecham Group Plc Paraherquamide derivatives, precursor thereof, processes for their preparation, microorganism used and their use as antiparasitic agents
US5345377A (en) 1992-10-30 1994-09-06 Electric Power Research Institute, Inc. Harmonic controller for an active power line conditioner
GB9300883D0 (en) 1993-01-18 1993-03-10 Pfizer Ltd Antiparasitic agents
US5399582A (en) 1993-11-01 1995-03-21 Merck & Co., Inc. Antiparasitic agents
DE4405898A1 (de) * 1994-02-18 1995-08-24 Schering Ag Transdermale therapeutische Systeme enthaltend Sexualsteroide
AUPM969994A0 (en) 1994-11-28 1994-12-22 Virbac S.A. Equine anthelmintic formulations
US5962499A (en) 1995-03-20 1999-10-05 Merck & Co., Inc. Nodulisporic acid derivatives
US6221894B1 (en) 1995-03-20 2001-04-24 Merck & Co., Inc. Nodulisporic acid derivatives
TW334436B (en) 1995-07-21 1998-06-21 Upjohn Co Antiparasitic marcfortines and paraherquamides
FR2739255B1 (fr) 1995-09-29 1998-09-04 Rhone Merieux Composition antiparasitaire pour le traitement et la protection des animaux de compagnie
US6010710A (en) 1996-03-29 2000-01-04 Merial Direct pour-on skin solution for antiparasitic use in cattle and sheep
IE80657B1 (en) 1996-03-29 1998-11-04 Merial Sas Insecticidal combination to control mammal fleas in particular fleas on cats and dogs
US5885607A (en) 1996-03-29 1999-03-23 Rhone Merieux N-phenylpyrazole-based anti-flea and anti-tick external device for cats and dogs
FR2752525B1 (fr) 1996-08-20 2000-05-05 Rhone Merieux Procede de lutte contre les myiases des cheptels bovins et ovins et compositions pour la mise en oeuvre de ce procede
US6998131B2 (en) 1996-09-19 2006-02-14 Merial Limited Spot-on formulations for combating parasites
US6426333B1 (en) 1996-09-19 2002-07-30 Merial Spot-on formulations for combating parasites
FR2753377B1 (fr) 1996-09-19 1999-09-24 Rhone Merieux Nouvelle association parasiticide a base de 1-n-phenylpyra- zoles et de lactones macrocycliques endectocides
US6207647B1 (en) 1997-07-18 2001-03-27 Smithkline Beecham Corporation RatA
JPH1149669A (ja) * 1997-08-05 1999-02-23 Nitto Denko Corp 抗ウイルス剤含有テープ製剤
JP4237293B2 (ja) * 1998-05-19 2009-03-11 東光薬品工業株式会社 経皮吸収型貼付剤
US6174540B1 (en) 1998-09-14 2001-01-16 Merck & Co., Inc. Long acting injectable formulations containing hydrogenated caster oil
PE20011289A1 (es) 2000-04-07 2001-12-21 Upjohn Co Composiciones antihelminticas que comprenden lactonas macrociclicas y espirodioxepinoindoles
CA2311881C (en) 2000-06-16 2007-08-28 Gary O. Maupin Control of arthropods in rodents
US6399786B1 (en) 2000-07-14 2002-06-04 Merck & Co., Inc. Nonacyclic nodulisporic acid derivatives
AR042420A1 (es) 2002-09-11 2005-06-22 Novartis Ag Benzotriazolil- aminoacetonitril compuestos, proceso para su preparacion, metodo y uso de los mismos en el control de endo- y ecto-parasitos dentro y sobre ganado productor de sangre caliente y animales domesticos y plantas, y en la preparacion de una composicion farmaceutica
US9265725B2 (en) * 2002-10-25 2016-02-23 Foamix Pharmaceuticals Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
US7262214B2 (en) 2003-02-26 2007-08-28 Merial Limited 1-N-arylpyrazole derivatives in prevention of arthropod-borne and mosquito-borne diseases
JP2004269368A (ja) * 2003-03-05 2004-09-30 Ogawa & Co Ltd 冷感剤組成物および該冷感剤組成物を含有する冷感化粧料
MXPA05010659A (es) 2003-04-04 2005-12-12 Merial Ltd Formulaciones veterinarias antihelminticas topicas.
JP4405765B2 (ja) * 2003-08-04 2010-01-27 大阪化成株式会社 屋内性防ダニ剤
WO2005034952A2 (en) 2003-10-07 2005-04-21 The Feinstein Institute For Medical Research Isoxazole and isothiazole compounds useful in the treatment of inflammation
US7531186B2 (en) 2003-12-17 2009-05-12 Merial Limited Topical formulations comprising 1-N-arylpyrazole derivatives and amitraz
SI1731512T1 (sl) 2004-03-05 2015-01-30 Nissan Chemical Industries, Ltd. Z izoksazolinom substituirana benzamidna spojina in sredstvo za uravnavanje škodljivih organizmov
US20050232876A1 (en) * 2004-04-19 2005-10-20 Robin Lynn Minga Skin care compositions
TWI350728B (en) * 2004-10-08 2011-10-21 Wyeth Corp Amitraz compositions
CA2610662A1 (en) * 2005-05-09 2007-05-18 Foamix Ltd. Foamable vehicle and pharmaceutical compositions thereof
US20060293260A1 (en) * 2005-05-24 2006-12-28 Wyeth Useful high load concentrate compositions for control of ecto-and endo-parasites
EP1932836B1 (en) 2005-09-02 2013-11-06 Nissan Chemical Industries, Ltd. Isoxazoline-substituted benzamide compound and harmful organism-controlling agent
WO2007070606A2 (en) 2005-12-14 2007-06-21 E. I. Du Pont De Nemours And Company Isoxazolines for controlling invertebrate pests
TW200803740A (en) 2005-12-16 2008-01-16 Du Pont 5-aryl isoxazolines for controlling invertebrate pests
TWI412322B (zh) 2005-12-30 2013-10-21 Du Pont 控制無脊椎害蟲之異唑啉
EP2005959B1 (en) 2006-03-08 2015-01-21 Nihon Nohyaku Co., Ltd. Pharmaceutical composition for external use
ES2344027T3 (es) 2006-03-10 2010-08-16 Nissan Chemical Industries, Ltd. Compuesto de isoxazolina sustituido y agente de control de plagas.
KR20090005201A (ko) 2006-04-20 2009-01-12 이 아이 듀폰 디 네모아 앤드 캄파니 무척추 해충 방제용 피라졸린
JP2008044880A (ja) 2006-08-15 2008-02-28 Bayer Cropscience Ag 殺虫性イソオキサゾリン類
CN101583278B (zh) * 2006-09-01 2013-07-10 杜邦公司 包含茚虫威的局部外用给药制剂
US8303856B2 (en) 2007-02-26 2012-11-06 Lg Chem, Ltd. Conductive laminated body and method for preparing the same
EP2151437A4 (en) 2007-03-07 2012-05-02 Nissan Chemical Ind Ltd ISOXAZOLINE SUBSTITUTED BENZAMIDE COMPOUND AND PEST CONTROL AGENT
JP5256753B2 (ja) 2007-03-29 2013-08-07 住友化学株式会社 イソオキサゾリン化合物とその有害生物防除用途
BRPI0810196A2 (pt) 2007-04-10 2011-12-06 Bayer Cropscience Ag inseticidas de derivados de aril isoxazolina
DK2639228T3 (en) 2007-05-15 2016-09-12 Merial Inc Aryloazol-2-yl-cyanoethylaminoforbindelser, method of making and method of use thereof
US8623875B2 (en) 2007-06-13 2014-01-07 E.I. Du Pont De Nemours And Company Isoxazoline insecticides
EP2455755A3 (en) 2007-06-22 2012-08-15 GENERA ISTRAZIVANJA d.o.o. Proteaoglycan-4 as marker for chronic renal failure
TWI430995B (zh) * 2007-06-26 2014-03-21 Du Pont 萘異唑啉無脊椎有害動物控制劑
BRPI0810929B8 (pt) 2007-06-27 2022-12-06 Du Pont uso de um composto de fórmula 1
US8053452B2 (en) 2007-06-29 2011-11-08 Nissan Chemical Industries, Ltd. Substituted isoxazoline or enone oxime compound, and pest control agent
PT2170321E (pt) 2007-06-29 2013-08-01 Zoetis Llc Combinação anti-helmíntica
CN101854926A (zh) 2007-07-31 2010-10-06 惠氏有限责任公司 局部用杀体内寄生虫组合物
TWI556741B (zh) 2007-08-17 2016-11-11 英特威特國際股份有限公司 異唑啉組成物及其作為抗寄生蟲藥上的應用
TW200924647A (en) 2007-08-30 2009-06-16 Schering Plough Ltd Local topical administration formulations containing fipronil
JP5365806B2 (ja) 2007-09-10 2013-12-11 日産化学工業株式会社 置換イソキサゾリン化合物及び有害生物防除剤
US8367584B2 (en) 2007-10-03 2013-02-05 E.I. Du Pont De Nemours And Company Naphthalene isoxazoline compounds for control of invertebrate pests
US8597688B2 (en) 2008-07-09 2013-12-03 Basf Se Pesticidal mixtures comprising isoxazoline compounds II
EP2306837B2 (en) 2008-07-09 2023-10-25 Basf Se Pesticidal active mixtures comprising isoxazoline compounds i
EA201100421A1 (ru) 2008-09-04 2011-10-31 Зингента Партисипейшнс Аг Инсектицидные соединения
AU2009307736B2 (en) 2008-10-21 2015-02-05 Boehringer Ingelheim Animal Health USA Inc. Thioamide compounds, method of making and method of using thereof
WO2010079077A1 (en) 2008-12-18 2010-07-15 Novartis Ag Isoxazolines derivatives and their use as pesticide
EA201100980A1 (ru) 2008-12-23 2012-01-30 Басф Се Замещенные амидиновые соединения для подавления животных-вредителей
US20110288089A1 (en) 2009-01-22 2011-11-24 Syngenta Crop Protection Llc Insecticidal compounds
CN102369199A (zh) 2009-04-01 2012-03-07 巴斯夫欧洲公司 用于防治无脊椎动物害虫的异*唑啉化合物
WO2011000210A1 (zh) 2009-07-01 2011-01-06 润和生物医药科技(汕头)有限公司 促渗剂组合物及其透皮给药系统中的应用
TWI487486B (zh) 2009-12-01 2015-06-11 Syngenta Participations Ag 以異唑啉衍生物為主之殺蟲化合物
RS54772B1 (sr) 2009-12-17 2016-10-31 Merial Sas Antiparazitska jedinjenja dihidroazola i kompozicije koje ih sadrže
EP2531493B1 (en) 2010-02-01 2015-07-22 Basf Se Substituted ketonic isoxazoline compounds and derivatives for combating animal pests
EA022116B1 (ru) 2010-02-25 2015-11-30 Зингента Партисипейшнс Аг Пестицидные смеси, включающие изоксазолиновые производные и инсектицид
UA108641C2 (uk) 2010-04-02 2015-05-25 Паразитицидна композиція, яка містить чотири активних агенти, та спосіб її застосування
HUE028501T2 (en) * 2010-05-27 2016-12-28 Du Pont 4- [5- [3-Chloro-5- (trifluoromethyl) phenyl] -4,5-dihydro-5- (trifluoromethyl) -3-isoxazolyl] -N- [2-oxo-2 - [(2.2, 2-Trifluoroethyl) amino] ethyl] -1-naphthalenecarboxamide crystalline form
US20130261069A1 (en) 2010-06-09 2013-10-03 Syngenta Crop Protection Llc Pesticidal mixtures comprising isoxazoline derivatives
US20130203591A1 (en) 2010-06-09 2013-08-08 Syngenta Crop Protection Llc Pesticidal mixtures including isoxazoline derivatives
US20130210623A1 (en) 2010-06-09 2013-08-15 Syngenta Crop Protection Llc Pesticidal mixtures including isoxazoline derivatives
DK178277B1 (da) 2010-06-18 2015-10-26 Novartis Tiergesundheit Ag Diaryloxazolinforbindelser til bekæmpelse af fiskelus
WO2012007426A1 (en) 2010-07-13 2012-01-19 Basf Se Azoline substituted isoxazoline benzamide compounds for combating animal pests
CA2807005C (en) 2010-08-05 2015-04-07 Ah Usa 42 Llc Isoxazoline derivatives as antiparasitic agents
BR112013006686A2 (pt) 2010-09-24 2017-11-14 Zoetis Llc isoxazolina oximas como agentes antiparasitários
PT2658542T (pt) 2010-12-27 2022-03-10 Intervet Int Bv Formulação de isoxazolina localizada tópica
CN103260620A (zh) 2010-12-27 2013-08-21 英特维特国际股份有限公司 包含三缩四乙二醇的外用局部异噁唑啉制剂
EP3788874A1 (en) * 2011-09-12 2021-03-10 Boehringer Ingelheim Animal Health USA Inc. Parasiticidal compositions comprising an isoxazoline active agent, method and uses thereof
ME03323B (me) * 2012-02-06 2019-10-20 Merial Inc Paraziticidne oralne veterinarske kompozicije koje sadrže sistemski djelujuća aktivna sredstva, metodi i primjene istih

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040213744A1 (en) * 1999-05-20 2004-10-28 U & I Pharmaceuticals Ltd. Topical spray compositions

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